Download women in placebo [see Warnings and Precautions (5.1)].

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
OSPHENA safely and effectively. See full prescribing information for
OSPHENA.
OSPHENATM (ospemifene) tablets, for oral use
Initial U.S. Approval: 2013
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR
DISORDERS
See full prescribing information for complete boxed warning.
OSPHENA is an estrogen agonist/antagonist with tissue selective
effects. In the endometrium, OSPHENA has estrogen agonistic effects.
There is an increased risk of endometrial cancer in a woman with a
uterus who uses unopposed estrogens. Adding a progestin to estrogen
therapy reduces the risk of endometrial hyperplasia, which may be a
precursor to endometrial cancer [see Warnings and Precautions (5.2)].
Estrogen-alone therapy has an increased risk of stroke and deep vein
thrombosis (DVT). OSPHENA 60 mg had cerebral thromboembolic
and hemorrhagic stroke incidence rates of 0.72 and 1.45 per thousand
women, respectively vs. 1.04 and 0 per thousand women, respectively
in placebo. For deep vein thrombosis, the incidence rate for
OSPHENA 60 mg is 1.45 per thousand women vs. 1.04 per thousand
women in placebo [see Warnings and Precautions (5.1)].
--------------INDICATIONS AND USAGE--------------------OSPHENA is an estrogen agonist/antagonist indicated for the treatment of
moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy,
due to menopause (1)



---------------WARNINGS AND PRECAUTIONS-----------
Venous Thromboembolism: Risk of DVT and pulmonary embolism
(5.1)

Known, suspected, or history of breast cancer (5.2)

Severe Hepatic Impairment (5.3, 8.7, 12.3)
-------------------ADVERSE REACTIONS----------------------
Adverse reactions (≥1 percent) include: hot flush, vaginal discharge, muscle
spasms, genital discharge, hyperhidrosis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc.
at 1-855-OSPHENA (1-855-677-4362) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS---------------------
Do not use estrogens or estrogen agonist/antagonist concomitantly with
OSPHENA (7.1,12.3)

Do not use fluconazole concomitantly with OSPHENA. Fluconazole
increases serum concentrations of OSPHENA (7.2, 12.3)

Do not use rifampin concomitantly with OSPHENA. Rifampin decreases
serum concentration of OSPHENA (7.2, 12.3)
-------------USE IN SPECIFIC POPULATIONS-------------
------------DOSAGE AND ADMINISTRATION------------
One tablet taken orally once daily with food (2.1)
-----------DOSAGE FORMS AND STRENGTHS------------
Tablet: 60 mg (3)

Undiagnosed abnormal genital bleeding (4)

Known or suspected estrogen-dependent neoplasia (4, 5.2)
Revised: 02/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR
DISORDERS
1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of
Vulvar and Vaginal Atrophy, due to Menopause
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Disorders
5.2 Malignant Neoplasms
5.3 Severe Hepatic Impairment
6. ADVERSE REACTIONS
6.1 Clinical Trials Experience
7. DRUG INTERACTIONS
7.1 Estrogens and estrogen agonist/antagonist
7.2 Fluconazole
7.3 Rifampin
7.4 Ketoconazole
7.5 Warfarin
7.6 Highly Protein-Bound Drugs
7.7 Multiple Enzyme Inhibition
8. USE IN SPECIFIC POPULATIONS
Nursing Mothers: It is not known whether OSPHENA is excreted in
human breast milk (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling
---------------------CONTRAINDICATIONS------------------
Active DVT, pulmonary embolism (PE), or a history of these conditions
(4, 5.1)
Active arterial thromboembolic disease (for example, stroke and
myocardial infarction [MI]), or a history of these conditions (4, 5.1)
Known or suspected pregnancy (4, 8.1)
10.
11.
12.
13.
14.
16.
17.
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
PATIENT COUNSELING INFORMATION
17.1 Hot Flashes or Flushes
17.2 Vaginal Bleeding * Sections or subsections omitted from the Full Prescribing Information are
not listed.
OSPH
HENATM (OSPEM
MIFENE)
FULL PRESCRIBING
G INFORMATION
N
WAR
RNING: ENDOM
METRIAL CANC
CER AND CARDIIOVASCULAR
DISORDE
ERS
Endometrial Cancer
OSPH
HENA is an estrog
gen agonist/antag
gonist with tissuee selective effects.
In the endometrium, OSPHENA
O
has esstrogen agonisticc effects. There iss
an inccreased risk of en
ndometrial canceer in a woman with
w
a uterus who
o
uses u
unopposed estro
ogens. Adding a progestin to estrogen
e
therapy
y
reducees the risk of endometrial hyperpllasia, which may be a precursor to
o
endom
metrial cancer. Adequate
A
diagnosstic measures, in
ncluding directed
d
and raandom endometriial sampling when
n indicated, shou
uld be undertaken
n
to rulle out malignanccy in postmenop
pausal women with
w
undiagnosed
d
persisttent or recurring abnormal gen
nital bleeding [seee Warnings and
d
Precau
utions (5.2)].
Cardiovascular Disorders
There is a reported in
ncreased risk of stroke and deep vein thrombosiss
(DVT)) in postmenopau
usal women (50 to 79 years of ag
ge) who received
d
daily ooral conjugated estrogens (CE) [0.625 mg]-alone therapy over 7.1
1
years aas part of the Wo
omen’s Health In
nitiative (WHI) [ssee Warnings and
d
Precau
utions (5.1)].
In thee clinical trials for
f OSPHENA (duration
(
of trea
atment up to 15
5
month
hs), the incidence rates of thrombo
oembolic and hem
morrhagic strokee
were 00.72 and 1.45 perr thousand women, respectively in
i OSPHENA 60
0
mg trreatment group and 1.04 and 0 in placebo [seee Warnings and
d
Precau
utions (5.1)]. The incidence of DVT
T was 1.45 per tho
ousand women in
n
OSPH
HENA 60 mg treeatment group an
nd 1.04 per thousand women in
n
placeb
bo [see Warningss and Precautions (5.1)]. OSPH
HENA should bee
prescrribed for the shorrtest duration consistent with trea
atment goals and
d
risks ffor the individual woman.
1. IN
NDICATIONS AN
ND USAGE
OSPHE
ENA is indicated for
f the treatment of
o moderate to seveere dyspareunia, a
symptoom of vulvar and vaginal
v
atrophy, du
ue to menopause.
2. DO
OSAGE AND AD
DMINISTRATIO
ON
OSPHE
ENA is an estrog
gen agonist/antago
onist which has ag
gonistic effects on
n
the enddometrium. Generrally, when a prod
duct with estrogen
n agonistic effectss
on the endometrium is prescribed
p
for a po
ostmenopausal wom
man with a uterus,
onsidered to reducce the risk of endo
ometrial cancer. A
a progestin should be co
us does not need
d a progestin [seee Warnings and
d
womann without a uteru
Precauutions (5.2)].
Use oof OSPHENA should be for the shortest duration
n consistent with
h
treatmeent goals and risk
ks for the individu
ual woman. Postm
menopausal women
n
shouldd be re-evaluated periodically
p
as cliinically appropriaate to determine iff
treatmeent is still necessarry.
2.1 Treatment of Modeerate to Severe Dy
yspareunia, a Sym
mptom of Vulvar
d to Menopausee
and Vaaginal Atrophy, due
OSPH
HENATM (OSPEM
MIFENE)
 OSPH
HENA is contrainddicated in womenn who are or mayy become pregnant.
OSPH
HENA may cause fetal harm when administered to a pregnant woman
n.
Ospem
mifene was embryyo-fetal lethal withh labor difficultiess and increased pu
up
deathss in rats at doses below clinical exxposures, and embbryo-fetal lethal in
rabbitss at 10 times the cclinical exposure bbased on mg/m2. If this drug is used
duringg pregnancy, or if a woman becomess pregnant while taaking this drug, sh
he
shouldd be apprised of thhe potential hazardd to a fetus.
5. W
WARNINGS AND
D PRECAUTION
NS
5.1 Caardiovascular Dissorders
Risk factors for carddiovascular disordders, arterial vascular disease (fo
or
a,
exampple, hypertension, diabetes mellitus, tobacco use, hyppercholesterolemia
and obbesity) and/or vennous thromboembolism (VTE) (for example, persona
al
historyy or family historyy of VTE, obesity, and systemic luppus erythematosus),
shouldd be managed apprropriately.
Strokee
In thee WHI estrogen-allone substudy, a sstatistically signifiicant increased risk
E
of strooke was reported in women 50 to 79 years of age rreceiving daily CE
(0.6255 mg)-alone com
mpared to women in the same agge group receivin
ng
placebbo (45 versus 33 per ten thousand women-years). T
The increase in risk
was deemonstrated in yeaar 1 and persisted.
In thee clinical trials forr OSPHENA (duraation of treatmentt up to 15 months),
the inccidence rates of thhromboembolic annd hemorrhagic strroke were 0.72 and
1.45 pper thousand wom
men, respectively inn OSPHENA 60 m
mg treatment grou
up
and 1..04 and 0 per thoussand women in plaacebo.
Shouldd thromboembolicc or hemorrhagic sstroke occur or be suspected,
OSPH
HENA should be diiscontinued immeddiately.
Coronnary Heart Diseasee
In thee WHI estrogen-aalone substudy, nno overall effect on coronary hearrt
diseasse (CHD) events (ddefined as nonfataal MI, silent MI, oor CHD death) wa
as
he
reportted in women recceiving estrogen-aalone compared tto placebo. In th
HENA clinical triaals, a single MI occcurred in a womaan receiving 60 mg
m
OSPH
of osppemifene.
Venouus Thromboemboliism
In thee WHI estrogen-aalone substudy, thhe risk of VTE (D
DVT and PE), wa
as
increaased for women receiving daily C
CE (0.625 mg)-aalone compared to
t
placebbo (30 versus 22 per ten thousandd women-years), although only th
he
increaased risk of DVT reached statisticaal significance (233 versus 15 per ten
thousaand women-years)). The increase inn VTE risk was deemonstrated durin
ng
the firrst 2 years.
In the OSPHENA cliniccal trials, the inciddence of DVT wass 1.45 per thousan
nd
womeen in OSPHENA 660 mg treatment ggroup and 1.04 peer thousand women
PHENA should be
b
in plaacebo. Should a VTE occur or bee suspected, OSP
disconntinued immediateely.
Take oone 60 mg tablet with
w food once daily
y.
If feassible, OSPHENA should be disconntinued at least 4 to 6 weeks beforre
surgerry of the type assoociated with an inccreased risk of thrromboembolism, or
o
duringg periods of prolonnged immobilizatioon.
3. DO
OSAGE FORMS AND STRENGT
THS
5.2 M
Malignant Neoplassms
OSPHE
ENA tablets are white
w
to off-white,, oval, biconvex, film
f
coated tabletss
containning 60 mg of ospeemifene and engraaved with “60” on one side.
Endom
metrial Cancer
4. CO
ONTRAINDICAT
TIONS
OSPHE
ENA is contraindiicated in women with
w any of the following conditions:

U
Undiagnosed abnorrmal genital bleeding

K
Known or suspecteed estrogen-depend
dent neoplasia

A
Active DVT, pulmonary embolism (P
PE), or a history of these conditions

A
Active arterial thro
omboembolic diseaase [for example, stroke
s
and
m
myocardial infarctiions (MI)], or a hisstory of these cond
ditions
OSPH
HENA is an estroggen agonist/antagoonist with tissue sselective effects. In
the enndometrium, OSPH
HENA has agonisttic effects. In the O
OSPHENA clinica
al
trials ((60 mg treatment group), no cases oof endometrial canncer were seen witth
exposuure up to 52 we eks. There was a single case of simple hyperplasiia
withouut atypia. Endomeetrial thickening equal to 5 mm or ggreater was seen in
the O SPHENA treatmeent groups at a raate of 60.1 per thousand women vss.
o
21.2 pper thousand woomen for placebo. The incidencee of any type of
prolifeerative (weakly pllus active plus dissordered) endomettrium was 86.1 pe
er
thousaand women in OS
SPHENA vs. 13.33 per thousand w
women for placebo
o.
Uterinne polyps occurredd at an incidence of 5.9 per thousandd women vs. 1.8 pe
er
thousaand women for plaacebo.
2
OSPH
HENATM (OSPEM
MIFENE)
HENATM (OSPEM
MIFENE)
OSPH
An inccreased risk of en
ndometrial cancer has been reporteed with the use off
unoppoosed estrogen th
herapy in a wom
man with a uterrus. The reported
d
endom
metrial cancer risk among unopposeed estrogen users is about 2 to 12
2
times greater than in non-users, and appears
a
dependen
nt on duration off
gen dose. Most stu
udies show no sig
gnificant increased
d
treatmeent and on estrog
risk associated with the use
u of estrogens fo
or less than 1 yearr. The greatest risk
k
appearrs to be associated with prolonged usse, with increased risks of 15- to 24-fold foor 5 to 10 years or more. This risk has
h been shown to persist for at leastt
8 to 15 years after estro
ogen therapy is discontinued.
d
Addiing a progestin to
o
b
shown to reeduce the risk off
postmeenopausal estrogeen therapy has been
endom
metrial hyperplasiaa, which may be a precursor to en
ndometrial cancer.
There are, however, po
ossible risks that may
m be associated
d with the use off
o estrogen-alone regimens. Thesee
progestins with estrogeens compared to
r
of breast can
ncer. The use of progestins with
h
includee an increased risk
OSPHE
ENA therapy was not evaluated in th
he clinical trials.
Tablee 1:
Clinicaal surveillance of all women using OSPHENA is imp
portant. Adequatee
diagnoostic measures, in
ncluding directed or random endo
ometrial sampling
g
when indicated, shou
uld be undertakeen to rule outt malignancy in
n
n with undiagnoseed persistent or reecurring abnormall
postmeenopausal women
genitall bleeding.
Breast Cancer
ENA 60 mg has not been adequately studied in women
w
with breastt
OSPHE
cancer; therefore, it should not be used in women with kn
nown or suspected
d
breast cancer or with a history of breast can
ncer.
5.3 Sevvere Hepatic Imp
pairment
OSPHE
ENA should not be
b used in women with
w severe hepatiic impairment [seee
Use in Specific Populatio
ons (8.7), and Clin
nical Pharmacolog
gy (12.3)].
Adverse Reactions Repoorted More Com
mmon in the
NA Treatment Grroup (60 mg Oncee Daily) and at
OSPHEN
Frequenccy ≥1.0% in th
he Double-Blind
d, Controlled
Clinical T
Trials with OSPH
HENA vs. Placeboo
Ospemifene 60 mg
Placebo
(N=1242)
(N=958)
%
%
7.5
2.6
Vaaginal discharge
3.8
0.3
enital discharge
Gen
1.3
0.1
3.2
0.9
1.6
0.6
Vascuular Disorders
Hoot flush
Reprooductive System annd Breast
Disordders
Muscuuloskeletal and Coonnective
Tissuee Disorders
Muuscle spasms
Skin aand Subcutaneous
Tissuee Disorders
Hyyperhidrosis
6. AD
DVERSE REACT
TIONS
7. D
DRUG INTERAC
CTIONS
The foollowing serious adverse reaction
ns are discussed elsewhere in thee
labelinng:
OSPH
HENA is primarilyy metabolized byy CYP3A4 and CY
YP2C9. CYP2C19
and otther pathways conttribute to the metaabolism of ospemiffene.
6.1

Cardiovascular Disorders [see Boxed
B
Warning, Warnings
W
and
Precautions (5.1)]
(

Malignant Neeoplasms [see Boxxed Warning, Warn
nings and
Precautions (5.2)]
(
Clinical Tria
als Experience
Becausse clinical trials arre conducted underr widely varying conditions,
c
adversee
reactioon rates observed in the clinical trials
t
of a drug cannot
c
be directly
y
compaared to rates in the clinical trials of another
a
drug and may
m not reflect thee
rates obbserved in practicee.
The saafety of OSPHENA
A has been assesseed in nine phase 2/3
2 trials (N=1892))
with ddoses ranging from
m 5 to 90 mg perr day. The duratio
on of treatment in
n
these sstudies ranged from
m 6 weeks to 15 months.
m
Most wom
men (N=1370) had
d
a treatm
ment period of at least 12 weeks, 40
09 had at least 52 weeks (1 year) off
exposuure.
The incidence rates of th
hromboembolic an
nd hemorrhagic strroke were 0.72 perr
ported case of thrromboembolic stro
oke) and 1.45 perr
thousannd women (1 rep
thousannd women (2 rep
ported cases of hemorrhagic strokee), respectively in
n
OSPHE
ENA 60 mg treaatment group and 1.04 and 0 per thousand women,
respecttively in placebo. The incidence off deep vein throm
mbosis (DVT) wass
1.45 per thousand womeen in OSPHENA 60 mg treatment group (2 reported
d
n placebo.
cases oof DVT) and 1.04 (1 case of DVT) in
Table 1 lists adverse reacctions occurring more
m frequently in the
t OSPHENA 60
0
mg treaatment group than
n in placebo and at a frequency ≥1%..
7.1 Esstrogens and estroogen agonist/antaagonist
OSPH
HENA should not be used concom
mitantly with estroogens and estrogen
agonissts/antagonists. T
The safety of conncomitant use off OSPHENA witth
estroggens and estrogen aagonists/antagonissts has not been stuudied.
7.2 Flluconazole
Fluconnazole, a moderaate CYP3A / stroong CYP2C9 / m
moderate CYP2C19
inhibittor, should not bbe used with OSP
PHENA. Fluconaazole increases th
he
system
mic exposure of oospemifene by 2.7-fold. Administrattion of fluconazolle
with ospemifene mayy increase the riisk of OSPHEN
NA-related adversse
Pharmacology (122.3)].
reactioons [see Clinical P
7.3 Riifampin
Rifam
mpin, a strong CY
YP3A4 / moderaate CYP2C9 / m
moderate CYP2C19
induceer, decreases the ssystemic exposuree of ospemifene bby 58%. Therefore
e,
co-adm
ministration of OS
SPHENA with drrugs such as rifam
mpin which induc
ce
CYP3 A4, CYP2C9 andd/or CYP2C19 acttivity would be exxpected to decreasse
ct
the syystemic exposure oof ospemifene, whhich may decreasee the clinical effec
[see C
Clinical Pharmacoology (12.3)].
7.4 Keetoconazole
Ketoc onazole, a strong CYP3A4 inhibitoor increases the syystemic exposure of
o
mifene by 1.4-foldd. Administrationn of ketoconazolee chronically witth
ospem
ospem
mifene may increasse the risk of OSPH
HENA-related advverse reactions [se
ee
Cliniccal Pharmacology (12.3)].
7.5 W
Warfarin
Repeaated administrationn of ospemifene haad no effect on thee pharmacokinetic
cs
of a ssingle 10 mg dosee of warfarin. No study was conduucted with multiplle
mifene on clottingg time such as th
he
doses of warfarin. Thee effect of ospem
ot
Internnational Normalizeed Ratio (INR) oor prothrombin tiime (PT) was no
studie d [see Clinical Phharmacology (12.33)].
3
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
7.6 Higghly Protein-Bou
und Drugs
8.7 Heepatic Impairmen
nt
Ospem
mifene is more thaan 99% bound to serum
s
proteins and might affect thee
proteinn binding of otherr drugs. Use of OSPHENA
O
with otther drug productss
that arre highly protein bound
b
may lead to
t increased expossure of either thatt
drug orr ospemifene [see Clinical Pharmaccology (12.3)].
The ppharmacokinetics of ospemifene haas not been studieed in women witth
severee hepatic impairm
ment (Child-Pughh Class C); therrefore, OSPHENA
A
shouldd not be used in w
women with severre hepatic impairm
ment [see Warning
gs
and Pr
Precautions (5.3), aand Clinical Pharm
macology (12.3)].
7.7 Mu
ultiple Enzyme In
nhibition
No cllinically importantt pharmacokineticc differences withh OSPHENA werre
men with mild too moderate hepatiic impairment an
nd
observved between wom
healthhy women [see Cliinical Pharmacoloogy (12.3)].
Co-adm
ministration of OS
SPHENA with a drug
d
known to inh
hibit CYP3A4 and
d
CYP2C
C9 isoenzymes may
m increase the risk of OSPHEN
NA-related adversee
reactioons.
8. US
SE IN SPECIFIC
C POPULATIONS
S
No doose adjustment off OSPHENA is reequired in womenn with mild (Child
dPugh C
Class A) or moderrate (Child-Pugh C
Class B) hepatic im
mpairment.
8.1 Preegnancy
10. O
OVERDOSAGE
Teratoogenic effects:
There is no specific antiidote for OSPHEN
NA.
Pregnaancy Category X [see
[s Contraindicatiions (4)].
Risk S
Summary
Based on animal data, OSPHENA is lik
kely to increase th
he risk of adversee
outcom
mes during pregnaancy and labor. Adverse
A
findings at
a maternally toxicc
doses iincluded embryofeetal lethality in rats and rabbits, and neonatal mortality
y
and difficult labor in raats. The reproductive effects observ
ved are consistentt
d to estrogen recceptor activity off
with aand are considereed to be related
OSPHE
ENA.
11. D
DESCRIPTION
OSPH
HENA is an estrogeen agonist/antagonnist. The chemicall structure of
ospem
mifene is shown in Figure 1.
Animaal Data
The efffects of OSPHEN
NA on embryo-fetaal development were
w
studied in ratss
(0.1, 1 or 4 mg/kg/day)) and rabbits (3, 10, or 30 mg/kg/d
day) when treated
d
mplantation throug
gh organogenesis. In rabbits, there was
w an increase in
n
from im
the inccidence of total resorptions at 30
0 mg/kg/day (10 times the human
n
exposuure based on surfface area mg/m2). Drug-induced maalformations weree
not obsserved in either ratts or rabbits.
The efffects of OSPHEN
NA on pre-and posstnatal developmen
nt were studied in
n
pregnaant rats (0.01, 0.0
05, and 0.25 mg//kg/day) treated from
f
implantation
n
throughh lactation. Pregn
nant rats given 0.05 or 0.25 mg/k
kg/day OSPHENA
A
(0.8% to 4% the humaan exposure baseed on surface areea mg/m2), had a
n
significcantly prolonged and difficult gesstation, increased post-implantation
loss, inncreased number of dead pups at birth,
b
and an increeased incidence off
postnattal loss. OSPHEN
NA did not inducce adverse effectss in the surviving
g
offspriing of pregnant ratts at drug exposurees up to 4% the hum
man exposure.
8.3 Nu
ursing Mothers
It is noot known whether OSPHENA
O
is excrreted in human breeast milk.
In a noonclinical study, ospemifene
o
was excreted
e
in rat millk and detected att
concenntrations higher thaan that in maternall plasma.
8.4 Ped
diatric Use
OSPHE
ENA is not indicatted in children. Clinical studies havee not been
conduccted in the pediatriic population.
hemical structuree
Figure 1: Ch
The
chemical
dessignation
is
1Z-2-[4-(4-chloro--1,2-diphenylbut-1
mpirical formula C24H23ClO2, which
enyl)pphenoxy]ethanol, and has the em
corressponds to a moleccular weight of 3778.9. Ospemifenee is a white to offfwhite crystalline powdeer that is insoluble in water and solubble in ethanol.
Each OSPHENA tablett contains 60 mg of ospemifene. Innactive ingredientts
e,
includde colloidal siliccon dioxide, hyypromellose, lacttose monohydrate
magneesium stearate, maannitol, microcrysttalline cellulose, ppolyethylene glycol,
povidoone, pregelatinizeed starch, sodium
m starch glycolate,, titanium dioxide
e,
and triiacetin.
12. C
CLINICAL PHA
ARMACOLOGY
12.1 M
Mechanism of Acttion
OSPH
HENA is an estroggen agonist/antagoonist with tissue selective effects. Itts
biologgical actions are m
mediated through binding to estroggen receptors. Thiis
bindinng results in activaation of estrogenicc pathways in som
me tissues (agonism
m)
and bllockade of estrogeenic pathways in otthers (antagonism)).
12.3 P
Pharmacokineticss
8.5 Geeriatric Use
Absorp
rption
Of the 1892 OSPHENA--treated women en
nrolled in the nine phase 2/3 trials off
ENA, >19 percen
nt were 65 yearss of age or oldeer. No clinically
y
OSPHE
meaninngful differences in safety or effectiv
veness were obserrved between thesee
womenn and younger wom
men less than 65 years
y
of age.
Follow
wing a single orral administrationn of OSPHENA 60 mg tablet in
postm
menopausal womeen under fastedd condition, peaak median serum
m
concenntrations was reacched at approxim
mately 2 hours (rannge: 1 to 8 hourss)
post-ddose (see Figure 2). Mean ospem
mifene Cmax and A
AUC0-inf were 533
ng/mL
L and 4165 ng•hr/m
mL, respectively. After a single oraal administration of
o
OSPH
HENA 60 mg tabblet in postmenoppausal women wiith a high fat/high
caloriee (860 kcal) meal, Cmax was reachedd at approximately 2.5 hours (range: 1
to 6 hoours) post-dose. M
Mean ospemifene Cmax and AUC0-innf were 1198 ng/mL
L
and 75521 ng•hr/mL, resspectively. The abbsolute bioavailability of ospemifen
ne
was not evaluated. Ospemifene exhhibits less than dose-proportiona
al
macokinetics from 25 to 200 mg w
with ospemifene caapsule formulation
n.
pharm
Accum
mulation of ospem
mifene with respeect to AUC0-inf waas approximately 2
after tw
welve weeks of daaily administrationn. Steady-state wass reached after nin
ne
days oof ospemifene adm
ministration.
8.6 Reenal Impairment
w
with severee renal impairmentt
The phharmacokinetics off ospemifene in women
(CrCL <30 mL/min) was
w similar to th
hose in women with
w
normal renall
harmacology (12.3
3)].
functioon [see Clinical Ph
No doose adjustment of
o OSPHENA iss required in women with renall
impairm
ment.
4
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
Figuree 2: Mean serum concentration
c
proffile of ospemifene following
f
a singlee
oral addministration of OSPHENA
O
60 mg ta
ablet in postmenop
pausal women
under ffed (N=28) and fa
asted (N=91) conditions
men with moderatte
compaared to women wiith normal hepaticc function. In wom
hepatiic impairment (C
Child-Pugh Classs B), the Cmax and AUC0-inf fo
or
ospem
mifene following a single 60 mg doose administered w
with a high fat/hig
gh
caloriee meal were higheer by 1% and 29%
%, respectively, coompared to women
with nnormal hepatic funnction. The effect of severe hepatic impairment on th
he
pharm
macokinetics of osspemifene has nott been evaluated [[see Warnings and
Precauutions (5.3), and U
Use in Specific Poppulations (8.7)].
Drug IInteractions
Ospem
mifene is metabollized primarily byy CYP3A4 and CYP2C9. CYP2C19
and otther pathways conntribute to the meetabolism of ospem
mifene. In order of
o
decreaasing potency, osspemifene was suuggested to be a weak inhibitor fo
or
CYP22B6, CYP2C9, CY
YP2C19, CYP2C88, CYP2D6 and C
CYP3A4 in in vitrro
i
studie s. Ospemifene is nnot a significant P--glycoprotein subsstrate in vitro; no in
was conducted.
vivo trransporter study w
Effect of Co-Administerred Drugs on the P
Pharmacokinetics oof Ospemifene
Food E
Effect
In geneeral, food increaseed the bioavailabillity of ospemifene by approximately
y
2-3 folld. In a cross-stud
dy comparison, sin
ngle dose OSPHE
ENA 60 mg tablett
adminiistered with a high
h fat/high calorie meal (860 kcal) in
i postmenopausall
womenn increased Cmax and AUC0-inf by
y 2.3- and 1.7-ffold, respectively,
compaared to fasted con
ndition. Eliminatio
on half-life and time
t
to maximum
m
concenntration (Tmax) weere unchanged in the presence of food.
f
In two food
d
effect studies in healthy males using diffeerent ospemifene tablet
t
formulationss
d 1.8-fold, respecttively, with a low
w
Cmax annd AUC0-inf increeased by 2.3- and
fat/low
w calorie meal (300
(
kcal) and increased by 3..6- and 2.7-fold,
respecttively, with a high
h fat/high calorie meal
m (860 kcal), compared
c
to fasted
d
conditiion. OSPHENA
A should be tak
ken with food [see
[
Dosage and
d
Administration (2.1)].
Distribbution
OSPHE
ENA is highly (>
>99 percent) boun
nd to serum proteeins. The apparentt
volumee of distribution iss 448 L.
Metaboolism
In vitroo experiments witth human liver microsomes indicateed that ospemifenee
primarrily undergoes mettabolism via CYP
P3A4, CYP2C9 an
nd CYP2C19. Thee
major metabolite was 4-hydroxyospem
mifene. The apparent total body
y
a
clearannce is 9.16 L/hr using a population approach.
Excretion
h
of ospem
mifene in postmeno
opausal women iss
The appparent terminal half-life
approxximately 26 hourss. Following an oral administratio
on of ospemifene,
approxximately 75% and
d 7% of the dosee was excreted in
n feces and urine,
respecttively. Less than 0.2%
0
of the ospem
mifene dose was ex
xcreted unchanged
d
in urine.
ons
Use in Specific Populatio
Pediatrric
The pharmacokinetics of ospemifene in
n pediatric patien
nts has not been
n
pecific Populationss (8.4)].
evaluatted [see Use in Sp
Geriatrric
No diffferences in ospem
mifene pharmacokiinetics were deteccted with regard to
o
age (raange 40 to 80 yearss) [see Use in Speccific Populations (8.5)].
(
Race
harmacokinetics.
Race ddid not have clinicaally relevant effectt on ospemifene ph
Renal IImpairment
In wom
men with severe renal
r
impairment (CrCL <30 mL/m
min), the Cmax and
d
AUC0-inf for ospemifenee following a sing
gle 60 mg dose ad
dministered with a
high ffat/high calorie meal
m
were loweer by 21% and higher by 20%,
respecttively [see Use in Specific Populatio
ons (8.6)].
Hepatiic Impairment
In wom
men with mild hep
patic impairment (Child-Pugh Classs A), the Cmax and
d
AUC0-inf for ospemifenee following a sing
gle 60 mg dose ad
dministered with a
high ffat/high calorie meal
m
were lower by 21% and 9..1%, respectively,
Fluconnazole (CYP3A4/C
CYP2C9/CYP2C199 Inhibitor)
Fluconnazole (a moderaate CYP3A / stroong CYP2C9 / m
moderate CYP2C19
inhibittor) 400 mg was given on Day 1 ffollowed by 200 m
mg on Days 2 to 5
under fasted condition. On Day 5 approoximately one houur after fluconazolle
es
adminnistration, ospemiffene 60 mg was addministered after brreakfast (two slice
of breead with ham, cheeese, a few slicess of cucumber and/or tomatoes, and
juice).. Fluconazole 2000 mg was taken fo
for three additionall days under fasted
condittion. Multiple dosses of fluconazole in fourteen postm
menopausal women
increaased the Cmax annd AUC0-inf of oospemifene by 11.7- and 2.7-fold
d,
respecctively [see Drug IInteractions (7.2)]].
Rifamppin (CYP3A4/CYP
P2C9/CYP2C19 Innducer)
Rifam
mpin 600 mg was ggiven once daily ffor 5 consecutive ddays (given at leasst
one hoour before or twoo hours after a meeal) in the late aft
fternoon. On Day 6
after aan overnight fast, ospemifene 60 m
mg was administerred in the mornin
ng
after uunder fed conditionn (two slices of brread with ham, cheeese, a few slices of
o
cucum
mber and/or tomatooes, and juice). M
Multiple doses of rrifampin 600 mg in
twelvee postmenopausal women reduced Cmax and AUC0-inff of ospemifene by
51% aand 58%, respecttively. Rifampin aand other inducerrs of CYP3A4 arre
expectted to decrease the systemic exxposure of ospem
mifene [see Drug
Interaactions (7.3)].
Ketocoonazole (CYP3A4 Inhibitor)
Ketoc onazole 400 mg was given once daily for 4 conssecutive days afte
er
breakffast. On Day 5 after an overnighht fast, ketoconaazole 400 mg an
nd
ospem
mifene 60 mg werre co-administeredd under fed condiition (two slices of
o
bread with ham, cheese,, a few slices of cuucumber and/or toomatoes, and juice).
ys
Ketoc onazole administrration once daily continued for ann additional 3 day
nd
(Days 6 to 8). Co-admiinistration of a sinngle 60 mg dose of ospemifene an
multipple doses of ketocconazole in twelvve postmenopausall women increased
Cmax aand AUC0-inf by 11.5- and 1.4-fold, respectively [see Drug Interaction
ns
(7.4)]..
Omeprrazole (CYP2C19 Inhibitor)
Omepprazole (a moderatte CYP2C19 inhiibitor) 40 mg wass given for 5 dayss.
Day 5, approxim
mately one hourr after omeprazoole administration
n,
On D
ospem
mifene 60 mg was administered afteer breakfast (two sslices of bread witth
ham, ccheese, a few slicces of cucumber aand/or tomatoes, aand juice). Multiplle
doses of omeprazole inn fourteen postmennopausal women increased Cmax an
nd
AUC00-inf by 1.20- and 1..17-fold, respectivvely.
Effect of Ospemifene onn the Pharmacokinnetics of the Co-Addministered Drug
Warfaarin
Ospem
mifene 60 mg wass given after a lighht breakfast (two sslices of bread witth
ham aand cheese and juiice) once daily forr 12 days in sixteen postmenopausa
al
womeen who were deetermined to bee rapid metaboliizers of CYP2C9
P2C9*1/*2). On Daay 8, a single dosee of warfarin 10 mg
m
(CYP22C9*1/*1 or CYP
and viitamin K 10 mg w
were administered one hour after a llight breakfast. Th
he
geomeetric mean ratio (990% CI) for S-waarfarin with and w
without ospemifen
ne
for Cmmax and AUC0-inf weere 0.97 (0.92-1.022) and 0.96 (0.91--1.02), respectively
y.
Multipple doses of ospem
mifene did not signnificantly affect the pharmacokinetic
cs
of a siingle dose of warrfarin. No study w
was conducted withh multiple doses of
o
warfarrin.
5
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
Omeprrazole
Ospem
mifene 60 mg was administered oncee daily for 7 days after a light meall
in the late afternoon in fourteen postmenopausal women. On
O Day 8 after an
n
o
was ad
dministered in thee
overnigght fast, a single 20 mg dose of omeprazole
morninng of at least 10 hrrs; ospemifene wass not given on Day
y 8. The geometricc
mean rratios for the metabolic index (omep
prazole/5-hydroxyo
omeprazole) at thee
concenntration at the 3 hr time point and for AUC0-8hr was
w 0.97 with and
d
withouut ospemifene. It is unclear if ospemifene will affect thee
pharmaacokinetics of dru
ugs metabolized by
b CYP2C19 due to the significantt
time gaap between ospem
mifene and omeprazzole administration
n.
postm
menopausal womenn between 41 to 811 years of age (meean 59 years of age
e)
who aat baseline had ≤5 percent superficiaal cells on a vaginnal smear, a vagina
al
pH >55.0, and who identtified at least one moderate to severre vaginal symptom
m
that w
was considered the most bothersomee to her (vaginal drryness, pain durin
ng
intercoourse [dyspareuniia], or vaginal irrritation/itching). Treatment group
ps
includded 30 mg OSPHE
ENA (n=282), 60 m
mg OSPHENA (n=
=276), and placebo
(n=26 8). All women weere assessed for im
mprovement in thee mean change from
m
Baseliine to Week 122 for the co-priimary efficacy vvariables of: mosst
botherrsome symptom ((MBS) of vulvar and vaginal atropphy (defined as th
he
individdual moderate to severe symptom tthat was identifiedd by the woman as
a
most bbothersome at baseline), percentagge of vaginal supeerficial and vagina
al
parabaasal cells on a vagginal smear, and vvaginal pH. Follow
wing completion of
o
12-weeeks, women withh an intact uterus w
were allowed to eenroll in a 40-week
doublee-blind extensionn study, and wom
men without an iintact uterus werre
alloweed to enroll in a 522-week open-labell extension study.
Buproppion
Ospem
mifene 60 mg was administered oncce daily for seven
n consecutive dayss
after thhe evening meal in sixteen postmeenopausal women (not homozygouss
for CY
YP2B6*6). On thee Day 8 after overrnight fast, a singlle 150 mg dose off
sustainned release bupro
opion was admin
nistered in morn
ning under fasted
d
conditiion. The geometricc mean ratio (90%
% CI) for bupropion
n with and withoutt
ospemiifene for Cmax and
d AUC0-inf were 0.8
82 (0.75-0.91) and
d 0.81 (0.77-0.86),
respecttively. The geomeetric mean ratio (90% CI) for hydrroxybupropion, an
n
active metabolite formed
d via CYP2B6, wiith and without osspemifene for Cmaxx
UC0-inf were 1.16 (1.09-1.24) and 0.9
98 (0.92-1.04), resp
pectively.
and AU
13. N
NONCLINICAL TOXICOLOGY
T
13.1 C
Carcinogenesis, Mutagenesis,
M
Impa
airment of Fertilitty
Carcinnogenesis
In a 2--year carcinogeniccity study in femaale mice, ospemifeene administration
n
of 1000, 400 or 1500 mg/kg/day was well tolerated. No
N evaluation forr
carcinoogenicity was cond
ducted in male micce. There was sign
nificant increase in
n
adrenaal subcapsular cell adenomas at 4 and
d 5 times the hum
man exposure based
d
on AU
UC, and adrenal co
ortical tumors at 5 times the human
n exposure. In thee
ovary, an increase in sex cord/stromal tumors, tubullostromal tumors,
a luteomas weree also seen. These findings occurred
d
granuloosa cell tumors, and
at dosees 2 to 5 times th
he human exposurre based on AUC, and are probably
y
relatedd to estrogenic/antiiestrogenic effect of
o ospemifene in mice.
m
In a 2--year carcinogenicity study in rats, ospemifene
o
adminiistration of 10, 50,
w tolerated. A siignificant increasee in thymomas wass
or 300 mg/kg/day was well
hymomas for femaales at all ospemiffene dose levels, orr
recordeed for males and th
0.3 to 1.2 times the hum
man exposure baseed on AUC. In thee liver, an increasee
in hepaatocellular tumorss were recorded att for females at all ospemifene dosee
levels.
Mutaggenesis
The seecond clinical triaal was a 12-week, randomized, douuble-blind, placebo
ocontroolled, parallel-grooup study that enrolled 919 generally health
hy
postm
menopausal womenn between 41 to 799 years of age (meean 59 years of age
e)
who aat baseline had ≤5 percent superficiaal cells on a vaginnal smear, a vagina
al
pH > 5.0, and who iddentified either m
moderate to severre vaginal drynesss
a
(dryneess cohort) or mooderate to severe ddyspareunia (dysppareunia cohort) as
most bothersome to hher at baseline. T
Treatment groupss included 60 mg
m
HENA (n=463) an
and placebo (n=4456). Primary enddpoints and stud
dy
OSPH
conduuct were similar to those in Trial 1.
The thhird clinical trial was a 52-week, randomized, doubble-blind, placebo
ocontroolled, long-term safety study thaat enrolled 426 generally healthy
postm
menopausal womenn between 49 to 799 years of age (meean 62 years of age
e)
with aan intact uterus. T
Treatment groups iincluded 60 mg O
OSPHENA (n=363
3)
and pllacebo (n=63).
Effectss on Dyspareunia
In thee 1st and 2nd clinnical trial, the moodified intent-to-ttreat population of
o
womeen treated with OS
SPHENA when coompared to placebbo, demonstrated a
ne
statistiically significant iimprovement (leasst square mean chaange from Baselin
to Weeek 12) in the modderate to severe m
most bothersome ssymptom (MBS) of
o
dysparreunia (1st trial p=
=0.0012, 2nd trial p<
<0.0001). See Tabble 2. A statistically
signifi
ficant increase in tthe proportion of ssuperficial cells annd a correspondin
ng
statistiically significant decrease in the proportion of paarabasal cells on a
vaginaal smear was allso demonstratedd (p<0.0001 for both). The mea
an
reducttion in vaginal pH
H between baselinee and Week 12 w
was also statisticallly
signifi
ficant (p<0.0001).
mifene was not genotoxic
g
in vitro
o in the Ames test
t
in strains off
Ospem
Salmonnella typhimurium
m or at the thym
midine kinase (tk)) locus of mousee
lymphooma L5178Y cellls in the absence and in the presen
nce of a metabolicc
activattor system. In in vivo testing, ospemifene was no
ot genotoxic in a
standarrd mouse bone maarrow micronucleu
us test or in a deterrmination of DNA
A
adductts in the liver of ratts.
Impairrment of Fertility
The eff
ffect of ospemifenee on fertility was not
n directly evaluatted. In female ratss
and m
monkeys, decreasess in ovarian and uterine weights, decreased
d
corporaa
lutea nnumber, increased ovarian cysts, utterine atrophy, and
d disrupted cycless
were oobserved when giv
ven repeated daily oral doses. In maale rats, atrophy off
the proostate and seminaal vesicles was noted. The effectts on reproductivee
organs observed in anim
mals are consistentt with the estrogen
n receptor activity
y
ntial for impairmen
nt of fertility.
of ospeemifene and poten
14. C
CLINICAL STUD
DIES
The efffectiveness and saafety of OSPHENA on moderate to
o severe symptomss
of vulvvar and vaginal atrophy in postmen
nopausal women were examined in
n
three pplacebo-controlled
d clinical trials (tw
wo 12-week efficaacy trials and onee
52-weeek long-term safetty trial). In the thrree placebo-contro
olled trials, a totall
of 787 women received placebo
p
and 1102 women received 60
6 mg OSPHENA..
w a 12-week, randomized,
r
doub
ble-blind, placebo-The first clinical trial was
oup study that enrolled 826 generally
g
healthy
y
controllled, parallel-gro
6
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
Table 2:
Vaginal Bleeding
17.2 V
Week 12 Effects on Dy
yspareunia (the Woman’s Self-me Moderate to Severe Symptom
m
Identified Most Bothersom
of Vulvar and Vaginal Atrrophy at Baselinee). Mean Changee
in Severitty at Week 12 with Last Obseervation Carried
d
Forward (LOCF),
(
Modified Intent-to-Treatt Populationa
Inform
m postmenopausaal women of thee importance of reporting unusua
al
vaginaal bleeding to thheir healthcare pproviders as soonn as possible [se
ee
Warniings and Precautioons (5.2)].
1st Clinical Trial Resullts
Most B
Bothersome Moderrate to
Severee Symptom at Baseeline
OSPHEN
NA 60 mg
Placebo
(N=110)
(N=113)
Dyspareeunia
Baseeline Mean (SD)
LS M
Mean Change from Baseline
B
(SE)
p-value vs. placebo
2.7 (0
0.44)
2.7
2 (0.45)
-1.39 (0.11)
(
-0
0.89 (0.11)
0.001
12
----
2nd Clinical Trial Results
Most Boothersome Moderatee to
Severe Symptom at Baselinee
OSPHEN
NA 60 mg
Placebo
(N=3
301)
(N=297)
Dyspareeunia
Baseline Mean (SD)
Mean Change from
LS M
Baseline (SE)
pp-value vs. placebo
a.
2.7 (0.47)
2.7 (0.47)
-1.55 (0
0.06)
-1.29 (0.07)
<0.000
01
---
T
The modified inten
nt-to-treat populatiion (mITT) includ
ded only women in
n
thhe ITT population who at baselin
ne met the inclusiion criteria of ≤5
5
ppercent superficial cells on a vaginal smear, a vaginal pH
p > 5.0, and who
o
iddentified moderatte or severe dyspareunia as her most bothersomee
vvaginal symptom.
Definittions: LOCF = lastt observation carriied forward; SD = standard
deviatiion; SE = standard
d error; LS = least square
16. H
HOW SUPPLIED
D/STORAGE AND
D HANDLING
16.1 H
How Supplied
OSPHE
ENA tablets are white
w
to off-white,, oval, biconvex, film
f
coated tabletss
containning 60 mg of osp
pemifene and eng
graved with “60” on
o one side. They
y
are avaailable as follows:
NDC 559630-580-10
Bottle off 100 tablets
NDC 559630-580-30
Blister pack of 30 tablets containing
c
2 blisterr
cards of 15 tablets each
16.2 Sttorage and Handling
Store aat 20º to 25ºC (68ºº to 77ºF); excursiions permitted to 15º
1 to 30ºC (59º to
o
86ºF) [[see USP Controlleed Room Temperaature].
17. P
PATIENT COUN
NSELING INFOR
RMATION
See FDA-apprroved patient labeling (Patient Information)
17.1 H
Hot Flashes or Flu
ushes
OSPHE
ENA may initiate or increase the occcurrence of hot flaashes in some
womenn.
7
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
Patient Information
and know th
he results. Do not take OSPH
HENA if the tes
st
is positive an
nd talk to yourr healthcare prrovider.
TM
OS
SPHENA (os
s fee’ nah)
(ospemiffene)
tabletts
Read this Patientt Information before you start taking
g
OSPH
HENA and each
h time you gett a refill. There
e may be new
w
inform
mation. This information does not take the place off
talkin
ng to your healthcare
h
pro
ovider about your medical
condition or your tre
eatment.
Wha
at is the most important in
nformation I should
kno
ow about OSP
PHENA ?

OSPHENA is a medicine th
hat works lik
ke estrogen
in the lining of the uterus
s (womb), but can work
differently in
n other parts of the body.

Taking estro
ogen-alone or
r OSPHENA may
m
increase you
ur chance of getting
g
cance
er of the
lining of the uterus (wom
mb). Vaginal bleeding
b
after menopause may be a warning sign of
cancer of the
e lining of the
e uterus (wom
mb). Your
healthcare provider
p
should check any unusual
vaginal bleed
ding to find out
o
the cause. Tell your
healthcare provider
p
rightt away if you have any
unusual vaginal bleeding while you ar
re taking
OSPHENA.
OSPHENA may increase your

y
chance of
o getting
strokes and blood clots.

You and your healthcare provider should talk
out whether you
y
still need
d
regularly abo
treatment with
w
OSPHENA
A.
at should I telll my healthcare provider before taking
g
Wha
OSPH
HENA?
Befo
ore you take O
OSPHENA, telll your health
hcare provider
if yo
ou:

have any u nusual vaginal bleeding
Vaginal blee
eding after me
enopause may
y be a warning
sign of cancer of the lining
g of the uterus
s (womb). You
ur
healthcare p
provider should
d check any u
unusual vagina
al
bleeding to ffind out the cause.

have any otther medical conditions
Such as seve
ere liver proble
ems.

are going t o have surge
ery or will be on bed rest
Your healthccare provider w
will let you know if you need
to stop takin
ng OSPHENA.

are breast ffeeding
It is not kno wn if OSPHENA
A can pass into
o your breast
milk.
care providerr about all m
medicines you
u
Tell your healthc
take
e, including pr escription and
d non-prescripttion medicines
s,
vitam
mins, and herrbal suppleme
ents. Some m
medicines may
affecct how OSPHE NA works. OS
SPHENA may a
also affect how
w
otherr medicines wo
ork. Keep a listt of your medicines and show
w
it to your healthca
are provider an
nd pharmacist each time you
get a new medicine
e.
Whatt is OSPHENA
A?
How
w should I tak
ke OSPHENA?
OSPH
HENA is an oral
o
prescriptio
on medicine used to treatt
painfu
ul intercourse, a symptom off changes in an
nd around yourr
vagina, due to menopause.

Take OSPH
HENA exactly h
how your healtthcare providerr
tells you to take it.

Take OSPH
HENA by moutth 1 time each day with food..
Who should not ta
ake OSPHENA
A?

You and y our healthcare
e provider shou
uld talk
regularly ((every 3 to 6 m
months) about the dose you
are taking
g and whether or not you stilll need
treatment with OSPHENA
A.
Do no
ot start taking OSPHENA if yo
ou:

have unusual vaginal ble
eeding
Vagin
nal bleeding affter menopause may be a warning
w
sign off
cance
er of the lining
g of the uteru
us (womb). Yo
our healthcare
e
provid
der should check any unusual vaginal bleeding to find
d
out th
he cause.

currently ha
ave or have had
h
certain ca
ancers
Estrogen ma
ay increase the
e chances of getting
g
certain
n
types of can
ncers, such as cancer of the
e lining of the
e
uterus. If yo
ou have or hav
ve had cancer, talk with yourr
healthcare provider
p
aboutt whether you
u should take
e
OSPHENA.

currently ha
ave or have had
h
blood clotts

had a stroke
e or heart atttack

think you may
m
be pregna
ant
OSPHENA is not for pregna
ant women. If you think you
u
may be preg
gnant, you should have a pregnancy
p
testt
Wha
at are the pos
ssible side efffects of OSPH
HENA?
See ““What is the most importa
ant informatio
on I should
know
w about OSPH
HENA?”
Serio
ous, but less common side
e effects inclu
ude:

stroke

blood clotss

cancer of tthe lining of th
he uterus (wom
mb)
Call your healthc
care provider right away iif you get any
y
of th
he following warning sig
gns or any o
other unusua
al
symp
ptoms that co
oncern you:

unusual va
aginal bleeding
g

changes in
n vision or speech

sudden ne
ew severe head
daches

severe paiins in your che
est or legs with
h or without
shortness of breath, wea
akness and fatigue
8
OSPH
HENATM (OSPEM
MIFENE)
OSPH
HENATM (OSPEM
MIFENE)
Less serious, but common side
e effects inclu
ude:
For more informa
ation, go to www.osphena.com or call
nogi Inc. at 1-8
855-OSPHENA
A (1-855-677-4
4362).
Shion

hot flushes
s or flashes

vaginal dis
scharge

muscle spa
asms

increased sweating
s
These
e are not all the
t
possible side effects of OSPHENA. Forr
more information, ask your healthcare provider orr
pharm
macist. Tell your healthcare provider ab
bout any side
e
effectts that bother you
y
or does no
ot go away.
Call y
your doctor for medical advice
e about side efffects. You
may rreport side effe
ects to FDA at 1-800-FDA-10
088.
Whatt can I do to lower my cha
ances of a ser
rious side
effec
ct with OSPHE
ENA?

Talk with your
y
healthcare
e provider regu
ularly about
whether yo
ou should continue taking OS
SPHENA.

If you have
e a uterus, talk
k with your hea
althcare
provider ab
bout whether the
t
addition of a progestin is
right for yo
ou.

See your healthcare
h
prov
vider right awa
ay if you
develop va
aginal bleeding while taking OSPHENA.
O

Have a pelvic exam, brea
ast exam and mammogram
m
(breast x-rray) every year unless your healthcare
h
provider te
ells you someth
hing else.

If memberrs of your familly have had bre
east cancer or
if you have
e ever had brea
ast lumps or an abnormal
mammogra
am (breast x-rray), you may need to have
breast exams more often
n.

If you have
e high blood prressure, high cholesterol
c
(fatt
in the blood), diabetes, are
a overweight, or use
tobacco, yo
ou may have a higher chance
e of getting
heart disea
ase.
Wha
at are the ingrredients in OSPHENA?
Activ
ve Ingredient: o
ospemifene
Inacttive ingredientss: colloidal silic
con dioxide, hy
ypromellose,
lacto se monohydra te, magnesium
m stearate, ma
annitol,
ocrystalline celllulose, polyeth
hylene glycol, p
povidone,
micro
prege
elatinized starcch, sodium starch glycolate, titanium
dioxi de, and triacettin.
This Patient Inform
mation has been
n approved by the U.S. Food
and D
Drug Administrration.
Manu
ufactured for:
Shion
nogi Inc.
Florh
ham Park, NJ 0
07932
Manu
ufactured by:
Penn
n Pharmaceuticcal Services Ltd
d.
23-24
4 Tafarnaubacch Industrial Es
state
Trede
egar, Gwent, S
South Wales
NP22
2 3AA, United K
Kingdom
Made
e in UK
OSP--PI-MKT-01
Appro
y 2013
oved: February
your healthcare
e provider for ways
w
to lower your
y
chances
Ask y
of gettting heart dise
ease.
How should I stor
re OSPHENA?
?
•
Store OSPH
HENA at room temperature between
b
68°F
to 77°F (20°C to 25
5°C).
Keep
p OSPHENA an
nd all medicin
nes out of the
e reach of
children.
Gene
eral informatiion about the
e safe and effe
ective use of
OSPH
HENA.
Medic
cines are sometimes prescribed for condiitions that are
e
not m
mentioned in patient inform
mation leaflets. Do not take
e
OSPH
HENA for condiitions for whic
ch it was not prescribed.
p
Do
o
not g
give OSPHENA
A to other peo
ople, even if they
t
have the
e
same
e symptoms you have. It may harm them.
This leaflet summarrizes the most important info
ormation aboutt
OSPH
HENA. If you would
w
like more
e information, talk with yourr
health
hcare provide
er or pharmacist. You can
c
ask yourr
health
hcare providerr or pharmacistt for more info
ormation aboutt
OSPH
HENA that is wrritten for health professionals
s.
9