Osphena
Generic Name: ospemifene
Dosage Form: tablet, film coated
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR
DISORDERS
Endometrial
Cancer
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. 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 [see Warnings
and Precautions (5.2)].
Cardiovascular
Disorders
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) [see Warnings and Precautions (5.1)].
In
the clinical trials for Osphena (duration of treatment up to 15 months), the
incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per
thousand women, respectively in Osphena 60 mg treatment group and 1.04 and 0 in
placebo [see Warnings and Precautions (5.1)]. The incidence of DVT was 1.45 per thousand women
in Osphena 60 mg treatment group and 1.04 per thousand women in placebo [see Warnings
and Precautions (5.1)]. Osphena should be prescribed for the shortest duration consistent with
treatment goals and risks for the individual woman.
1. INDICATIONS AND USAGE
Osphena is indicated for the treatment of moderate
to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to
menopause.
2. DOSAGE AND ADMINISTRATION
Osphena is an estrogen agonist/antagonist which has
agonistic effects on the endometrium. Generally, when a product with estrogen
agonistic effects on the endometrium is prescribed for a postmenopausal woman
with a uterus, a progestin should be considered to reduce the risk of
endometrial cancer. A woman without a uterus does not need a progestin [see Warnings
and Precautions (5.2)].
Use of Osphena should be for the shortest duration
consistent with treatment goals and risks for the individual woman.
Postmenopausal women should be re-evaluated periodically as clinically
appropriate to determine if treatment is still necessary.
Treatment of Moderate to Severe
Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause
Take one 60 mg tablet with food once daily.
3. DOSAGE FORMS AND STRENGTHS
Osphena tablets are white to off-white, oval,
biconvex, film coated tablets containing 60 mg of ospemifene and engraved with
"60" on one side.
4. CONTRAINDICATIONS
Osphena is contraindicated in women with any of the
following conditions:
Undiagnosed abnormal genital
bleedingKnown or suspected
estrogen-dependent neoplasiaActive DVT, pulmonary embolism
(PE), or a history of these conditionsActive arterial thromboembolic
disease [for example, stroke and myocardial infarctions (MI)], or a
history of these conditionsHypersensitivity
(for example, angioedema, urticaria, rash, pruritus) to Osphena or any
ingredientsOsphena is contraindicated in women
who are or may become pregnant. Osphena may cause fetal harm when
administered to a pregnant woman. Ospemifene was embryo-fetal lethal with
labor difficulties and increased pup deaths in rats at doses below
clinical exposures, and embryo-fetal lethal in rabbits at 10 times the
clinical exposure based on mg/m2. 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
5. WARNINGS AND PRECAUTIONS
Cardiovascular Disorders
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 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.
In the clinical trials for Osphena (duration of
treatment up to 15 months), the incidence rates of thromboembolic and
hemorrhagic stroke were 0.72 and 1.45 per thousand women, respectively in
Osphena 60 mg treatment group and 1.04 and 0 per thousand women in placebo.
Should thromboembolic or hemorrhagic stroke occur
or be suspected, Osphena should be discontinued immediately.
Coronary Heart Disease
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. In the Osphena clinical trials, a single MI occurred in a woman
receiving 60 mg of ospemifene.
Venous Thromboembolism
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.
In the Osphena clinical trials, the incidence of
DVT was 1.45 per thousand women in Osphena 60 mg treatment group and 1.04 per
thousand women in placebo. 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.
Malignant Neoplasms
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 treatment groups at a rate of 60.1 per thousand
women vs. 21.2 per thousand women for placebo. The incidence of any type of
proliferative (weakly plus active plus disordered) endometrium was 86.1 per
thousand women in Osphena vs. 13.3 per thousand women for placebo. Uterine
polyps occurred at an incidence of 5.9 per thousand women vs. 1.8 per thousand
women for placebo.
An increased risk of endometrial cancer has been
reported with the use of unopposed estrogen therapy in a woman with a uterus.
The reported endometrial cancer risk among unopposed estrogen users is about 2
to 12 times greater than in non-users, and appears dependent on duration of
treatment and on estrogen dose. Most studies show no significant increased risk
associated with the use of estrogens for less than 1 year. The greatest risk
appears to be associated with prolonged use, with increased risks of 15- to
24-fold for 5 to 10 years or more. This risk has been shown to persist for at
least 8 to 15 years after estrogen therapy is discontinued. Adding a progestin
to postmenopausal estrogen therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer. There
are, however, possible risks that may be associated with the use of progestins
with estrogens compared to estrogen-alone regimens. These include an increased
risk of breast cancer. The use of progestins with Osphena therapy was not
evaluated in the clinical trials.
Clinical surveillance of all women using Osphena is
important. Adequate diagnostic measures, including directed or random
endometrial sampling when indicated, should be undertaken to rule out
malignancy in postmenopausal women with undiagnosed persistent or recurring
abnormal genital bleeding.
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 or with a history of breast cancer.
Severe Hepatic Impairment
Osphena should not be used in women with severe
hepatic impairment [see Use
in Specific Populations (8.7),
and Clinical Pharmacology
(12.3)].
6. ADVERSE REACTIONS
The following serious adverse reactions are
discussed elsewhere in the labeling:
Cardiovascular Disorders [see
Boxed
Warning,
Warnings
and Precautions (5.1)]Malignant Neoplasms [see
Boxed
Warning,
Warnings
and Precautions (5.2)]
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
The safety of Osphena has been assessed in nine
phase 2/3 trials (N=1892) with doses ranging from 5 to 90 mg per day. The
duration of treatment in these studies ranged from 6 weeks to 15 months. Most
women (N=1370) had a treatment period of at least 12 weeks, 409 had at least 52
weeks (1 year) of exposure.
The incidence rates of thromboembolic and
hemorrhagic stroke were 0.72 per thousand women (1 reported case of
thromboembolic stroke) and 1.45 per thousand women (2 reported cases of
hemorrhagic stroke), respectively in Osphena 60 mg treatment group and 1.04 and
0 per thousand women, respectively in placebo. The incidence of deep vein
thrombosis (DVT) was 1.45 per thousand women in Osphena 60 mg treatment group
(2 reported cases of DVT) and 1.04 (1 case of DVT) in placebo.
Table 1 lists adverse reactions occurring more
frequently in the Osphena 60 mg treatment group than in placebo and at a
frequency ≥1%.
Table 1: Adverse Reactions Reported More Common in the Osphena
Treatment Group (60 mg Once Daily) and at Frequency ≥1.0% in the Double-Blind, Controlled Clinical
Trials with Osphena vs. Placebo
|
|
|
Ospemifene 60 mg
(N=1242)
%
|
Placebo
(N=958)
%
|
|
Vascular Disorders
|
|
Hot flush
|
7.5
|
2.6
|
|
Reproductive System and Breast Disorders
|
|
Vaginal
discharge
|
3.8
|
0.3
|
|
Genital
discharge
|
1.3
|
0.1
|
|
Musculoskeletal and Connective Tissue
Disorders
|
|
Muscle
spasms
|
3.2
|
0.9
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Hyperhidrosis
|
1.6
|
0.6
|
Postmarketing Experience
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.
Immune System Disorders: allergic
conditions including hypersensitivity, angioedema
Skin and Subcutaneous Tissue
Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria
7. DRUG INTERACTIONS
Osphena is primarily metabolized by CYP3A4 and
CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene.
Estrogens and estrogen
agonist/antagonist
Osphena should not be used concomitantly with estrogens
and estrogen agonists/antagonists. The safety of concomitant use of Osphena
with estrogens and estrogen agonists/antagonists has not been studied.
Fluconazole
Fluconazole, a moderate CYP3A / strong CYP2C9 /
moderate CYP2C19 inhibitor, should not be used with Osphena. Fluconazole
increases the systemic exposure of ospemifene by 2.7-fold. Administration of
fluconazole with ospemifene may increase the risk of Osphena-related adverse
reactions [see Clinical Pharmacology
(12.3)].
Rifampin
Rifampin, a strong CYP3A4 / moderate CYP2C9 /
moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%.
Therefore, co-administration of Osphena with drugs such as rifampin which induce
CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the
systemic exposure of ospemifene, which may decrease the clinical effect [see Clinical
Pharmacology (12.3)].
Ketoconazole
Ketoconazole, a strong CYP3A4 inhibitor increases
the systemic exposure of ospemifene by 1.4-fold. Administration of ketoconazole
chronically with ospemifene may increase the risk of Osphena-related adverse
reactions [see Clinical Pharmacology
(12.3)].
Warfarin
Repeated administration of ospemifene had no effect
on the pharmacokinetics of a single 10 mg dose of warfarin. No study was
conducted with multiple doses of warfarin. The effect of ospemifene on clotting
time such as the International Normalized Ratio (INR) or prothrombin time (PT)
was not studied [see Clinical
Pharmacology (12.3)].
Highly Protein-Bound Drugs
Ospemifene is more than 99% bound to serum proteins
and might affect the protein binding of other drugs. Use of Osphena with other
drug products that are highly protein bound may lead to increased exposure of
either that drug or ospemifene [see Clinical
Pharmacology (12.3)].
Multiple Enzyme Inhibition
Co-administration of Osphena with a drug known to
inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of Osphena-related
adverse reactions.
8. USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic effects:
Pregnancy Category X [see Contraindications
(4)].
Risk Summary
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.
Animal Data
The effects of Osphena 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. In rabbits,
there was an increase in the incidence of total resorptions at 30 mg/kg/day (10
times the human exposure based on surface area mg/m2). Drug-induced malformations were
not observed in either rats or rabbits.
The effects of Osphena on pre-and postnatal
development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day)
treated from implantation through lactation. Pregnant rats given 0.05 or 0.25
mg/kg/day Osphena (0.8% to 4% the human exposure based on 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. Osphena did not
induce adverse effects in the surviving offspring of pregnant rats at drug
exposures up to 4% the human exposure.
Nursing Mothers
It is not known whether Osphena is excreted in
human breast milk.
In a nonclinical study, ospemifene was excreted in
rat milk and detected at concentrations higher than that in maternal plasma.
Pediatric Use
Osphena is not indicated in children. Clinical
studies have not been conducted in the pediatric population.
Geriatric Use
Of the 1892 Osphena-treated women enrolled in the
nine 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.
Renal Impairment
The pharmacokinetics of ospemifene in women with
severe renal impairment (CrCL <30 mL/min) was similar to those in women with
normal renal function [see Clinical
Pharmacology (12.3)].
No dose adjustment of Osphena is required in women
with renal impairment.
Hepatic Impairment
The pharmacokinetics of ospemifene has not been
studied in women with severe hepatic impairment (Child-Pugh Class C);
therefore, Osphena should not be used in women with severe hepatic
impairment [see Warnings and Precautions
(5.3), and Clinical
Pharmacology (12.3)].
No clinically important pharmacokinetic differences
with Osphena were observed between women with mild to moderate hepatic
impairment and healthy women [see Clinical
Pharmacology (12.3)].
No dose adjustment of Osphena is required in women
with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic
impairment.
10. OVERDOSAGE
There is no specific antidote for Osphena.
11. DESCRIPTION
Osphena is an estrogen agonist/antagonist. The
chemical structure of ospemifene is shown in Figure 1.
Figure 1:
Chemical structure
The chemical designation is
Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, and has the empirical
formula C24H23ClO2, which corresponds to a molecular
weight of 378.9. Ospemifene is a white to off-white crystalline powder that is
insoluble in water and soluble in ethanol.
Each Osphena tablet contains 60 mg of ospemifene.
Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose
monohydrate, magnesium stearate, mannitol, microcrystalline cellulose,
polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate,
titanium dioxide, and triacetin.
12. CLINICAL PHARMACOLOGY
Mechanism of Action
Osphena is an estrogen agonist/antagonist with
tissue selective effects. Its biological actions are mediated through binding
to estrogen receptors. This binding results in activation of estrogenic
pathways in some tissues (agonism) and blockade of estrogenic pathways in
others (antagonism).
Pharmacokinetics
Absorption
Following a single oral administration of Osphena
60 mg tablet in postmenopausal women under fasted condition, peak median serum
concentrations was reached at approximately 2 hours (range: 1 to 8 hours)
post-dose (see Figure
2). Mean ospemifene Cmax and AUC0-inf were 533 ng/mL and 4165 ng∙hr/mL,
respectively. After a single oral administration of Osphena 60 mg tablet in
postmenopausal women with a high fat/high calorie (860 kcal) meal, Cmax was reached at
approximately 2.5 hours (range: 1 to 6 hours) post-dose. Mean ospemifene Cmax and AUC0-inf were 1198 ng/mL and
7521 ng∙hr/mL, respectively. The absolute bioavailability of ospemifene was not
evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics
from 25 to 200 mg with ospemifene capsule formulation. Accumulation of
ospemifene with respect to AUC0-inf was approximately 2 after twelve weeks of
daily administration. Steady-state was reached after nine days of ospemifene
administration.
|
Figure 2: Mean serum concentration profile of
ospemifene following a single oral administration of Osphena 60 mg tablet in
postmenopausal women under fed (N=28) and fasted (N=91) conditions
|
|
Food Effect
In general, food increased the bioavailability of
ospemifene by approximately 2-3 fold. In a cross-study comparison, single dose
Osphena 60 mg tablet administered with a high fat/high calorie meal (860 kcal)
in postmenopausal women increased Cmax and AUC0-inf by 2.3- and 1.7-fold,
respectively, compared to fasted condition. Elimination half-life and time to
maximum concentration (Tmax) were unchanged in the presence of food. In two
food effect studies in healthy males using different ospemifene tablet
formulations Cmax and AUC0-inf increased by 2.3-
and 1.8-fold, respectively, with a low fat/low calorie meal (300 kcal) and
increased by 3.6- and 2.7-fold, respectively, with a high fat/high calorie meal
(860 kcal), compared to fasted condition. Osphena should be taken with
food [see Dosage and Administration
(2.1)].
Distribution
Osphena
is highly (>99 percent) bound to serum proteins. The apparent volume of
distribution is 448 L.
Metabolism
In vitro experiments
with human liver microsomes indicated that ospemifene primarily undergoes
metabolism via CYP3A4, CYP2C9 and CYP2C19. The major metabolite was
4-hydroxyospemifene. The apparent total body clearance is 9.16 L/hr using a
population approach.
Excretion
The
apparent terminal half-life of ospemifene in postmenopausal women is
approximately 26 hours. Following an oral administration of ospemifene,
approximately 75% and 7% of the dose was excreted in feces and urine,
respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in
urine.
Use in Specific Populations
Pediatric
The
pharmacokinetics of ospemifene in pediatric patients has not been
evaluated [see Use in Specific Populations (8.4)].
Geriatric
No
differences in ospemifene pharmacokinetics were detected with regard to age
(range 40 to 80 years) [see Use in Specific Populations (8.5)].
Race
Race did
not have clinically relevant effect on ospemifene pharmacokinetics.
Renal Impairment
In women
with severe renal impairment (CrCL <30 mL/min), the Cmax and
AUC0-inf for ospemifene following a single 60 mg dose
administered with a high fat/high calorie meal were lower by 21% and higher by
20%, respectively [see Use in Specific Populations (8.6)].
Hepatic Impairment
In women
with mild hepatic impairment (Child-Pugh Class A), the Cmax and
AUC0-inf for ospemifene following a single 60 mg dose
administered with a high fat/high calorie meal were lower by 21% and 9.1%,
respectively, compared to women with normal hepatic function. In women with
moderate hepatic impairment (Child-Pugh Class B), the Cmax and
AUC0-inf for ospemifene following a single 60 mg dose
administered with a high fat/high calorie meal were higher by 1% and 29%,
respectively, compared to women with normal hepatic function. The effect of
severe hepatic impairment on the pharmacokinetics of ospemifene has not been
evaluated [see Warnings and Precautions (5.3), and Use in Specific Populations (8.7)].
Drug Interactions
Ospemifene
is metabolized primarily by CYP3A4 and CYP2C9. CYP2C19 and other pathways
contribute to the metabolism of ospemifene. In order of decreasing potency,
ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19,
CYP2C8, CYP2D6 and CYP3A4 in in vitro studies.
Ospemifene is not a significant P-glycoprotein substrate in
vitro; no in vivo transporter
study was conducted.
Effect of Co-Administered Drugs on the
Pharmacokinetics of Ospemifene
Fluconazole (CYP3A4/CYP2C9/CYP2C19 Inhibitor)
Fluconazole
(a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor) 400 mg was
given on Day 1 followed by 200 mg on Days 2 to 5 under fasted condition. On Day
5 approximately one hour after fluconazole administration, ospemifene 60 mg was
administered after breakfast (two slices of bread with ham, cheese, a few
slices of cucumber and/or tomatoes, and juice). Fluconazole 200 mg was taken
for three additional days under fasted condition. Multiple doses of fluconazole
in fourteen postmenopausal women increased the Cmax and
AUC0-inf of ospemifene by 1.7- and 2.7-fold,
respectively [see Drug Interactions (7.2)].
Rifampin (CYP3A4/CYP2C9/CYP2C19 Inducer)
Rifampin
600 mg was given once daily for 5 consecutive days (given at least one hour
before or two hours after a meal) in the late afternoon. On Day 6 after an
overnight fast, ospemifene 60 mg was administered in the morning after under
fed condition (two slices of bread with ham, cheese, a few slices of cucumber
and/or tomatoes, and juice). Multiple doses of rifampin 600 mg in twelve
postmenopausal women reduced Cmax and
AUC0-inf of ospemifene by 51% and 58%, respectively.
Rifampin and other inducers of CYP3A4 are expected to decrease the systemic exposure
of ospemifene [see Drug Interactions (7.3)].
Ketoconazole (CYP3A4 Inhibitor)
Ketoconazole
400 mg was given once daily for 4 consecutive days after breakfast. On Day 5
after an overnight fast, ketoconazole 400 mg and ospemifene 60 mg were
co-administered under fed condition (two slices of bread with ham, cheese, a
few slices of cucumber and/or tomatoes, and juice). Ketoconazole administration
once daily continued for an additional 3 days (Days 6 to 8). Co-administration
of a single 60 mg dose of ospemifene and multiple doses of ketoconazole in
twelve postmenopausal women increased Cmax and
AUC0-inf by 1.5- and 1.4-fold, respectively [see Drug Interactions (7.4)].
Omeprazole (CYP2C19 Inhibitor)
Omeprazole (a moderate CYP2C19 inhibitor) 40 mg was
given for 5 days. On Day 5, approximately one hour after omeprazole
administration, ospemifene 60 mg was administered after breakfast (two slices
of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and
juice). Multiple doses of omeprazole in fourteen postmenopausal women increased
Cmax and AUC0-inf by 1.20- and
1.17-fold, respectively.
Effect of Ospemifene on the
Pharmacokinetics of the Co-Administered Drug
Warfarin
Ospemifene 60 mg was given after a light breakfast
(two slices of bread with ham and cheese and juice) once daily for 12 days in
sixteen postmenopausal women who were determined to be rapid metabolizers of
CYP2C9 (CYP2C9*1/*1 or CYP2C9*1/*2). On Day 8, a single dose of warfarin 10 mg
and vitamin K 10 mg were administered one hour after a light breakfast. The
geometric mean ratio (90% CI) for S-warfarin with and without ospemifene for Cmax and AUC0-inf were 0.97
(0.92-1.02) and 0.96 (0.91-1.02), respectively. Multiple doses of ospemifene did
not significantly affect the pharmacokinetics of a single dose of warfarin. No
study was conducted with multiple doses of warfarin.
Omeprazole
Ospemifene 60 mg was administered once daily for 7
days after a light meal in the late afternoon in fourteen postmenopausal women.
On Day 8 after an overnight fast, a single 20 mg dose of omeprazole was
administered in the morning of at least 10 hrs; ospemifene was not given on Day
8. The geometric mean ratios for the metabolic index
(omeprazole/5-hydroxyomeprazole) at the concentration at the 3 hr time point
and for AUC0-8hr was 0.97 with and without ospemifene. It is
unclear if ospemifene will affect the pharmacokinetics of drugs metabolized by
CYP2C19 due to the significant time gap between ospemifene and omeprazole
administration.
Bupropion
Ospemifene 60 mg was administered once daily for
seven consecutive days after the evening meal in sixteen postmenopausal women
(not homozygous for CYP2B6*6). On the Day 8 after overnight fast, a single 150
mg dose of sustained release bupropion was administered in morning under fasted
condition. The geometric mean ratio (90% CI) for bupropion with and without
ospemifene for Cmax and AUC0-inf were 0.82
(0.75-0.91) and 0.81 (0.77-0.86), respectively. The geometric mean ratio (90%
CI) for hydroxybupropion, an active metabolite formed via CYP2B6, with and
without ospemifene for Cmax and AUC0-inf were 1.16
(1.09-1.24) and 0.98 (0.92-1.04), respectively.
13. NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis,
Impairment of Fertility
Carcinogenesis
In a 2-year carcinogenicity study in female mice,
ospemifene administration of 100, 400 or 1500 mg/kg/day was well tolerated. No
evaluation for carcinogenicity was conducted in male mice. There was
significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the
human exposure based on AUC, and adrenal cortical tumors at 5 times the human
exposure. In the ovary, an increase in sex cord/stromal tumors, tubulostromal
tumors, granulosa cell tumors, and luteomas were also seen. These findings
occurred at doses 2 to 5 times the human exposure based on AUC, and are
probably related to estrogenic/antiestrogenic effect of ospemifene in mice.
In a 2-year carcinogenicity study in rats,
ospemifene administration of 10, 50, or 300 mg/kg/day was well tolerated. A
significant increase in thymomas was recorded for males and thymomas for
females at all ospemifene dose levels, or 0.3 to 1.2 times the human exposure
based on AUC. In the liver, an increase in hepatocellular tumors were recorded
at for females at all ospemifene dose levels.
Mutagenesis
Ospemifene was not genotoxic in
vitro in
the Ames test in strains of Salmonella typhimurium or at the thymidine
kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the
presence of a metabolic activator system. In in
vivo testing,
ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test
or in a determination of DNA adducts in the liver of rats.
Impairment of Fertility
The effect of ospemifene on fertility was not directly
evaluated. In female rats and monkeys, decreases in ovarian and uterine
weights, decreased corpora lutea number, increased ovarian cysts, uterine
atrophy, and disrupted cycles were observed when given repeated daily oral
doses. In male rats, atrophy of the prostate and seminal vesicles was noted.
The effects on reproductive organs observed in animals are consistent with the
estrogen receptor activity of ospemifene and potential for impairment of
fertility.
14. CLINICAL STUDIES
The effectiveness and safety of Osphena on moderate
to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were
examined in three placebo-controlled clinical trials (two 12-week efficacy
trials and one 52-week long-term safety trial). In the three placebo-controlled
trials, a total of 787 women received placebo and 1102 women received 60 mg
Osphena.
The first clinical trial was a 12-week, randomized,
double-blind, placebo-controlled, parallel-group study that enrolled 826
generally healthy postmenopausal women between 41 to 81 years of age (mean 59
years of age) who at baseline had ≤5 percent superficial cells on a vaginal
smear, a vaginal pH >5.0, and who identified at least one moderate to severe
vaginal symptom that was considered the most bothersome to her (vaginal
dryness, pain during intercourse [dyspareunia], or vaginal irritation/itching).
Treatment groups included 30 mg Osphena (n=282), 60 mg Osphena (n=276), and
placebo (n=268). All women were assessed for improvement in the mean change
from Baseline to Week 12 for the co-primary efficacy variables of: most
bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the
individual moderate to severe symptom that was identified by the woman as most
bothersome at baseline), percentage of vaginal superficial and vaginal
parabasal cells on a vaginal smear, and vaginal pH. Following completion of
12-weeks, women with an intact uterus were allowed to enroll in a 40-week
double-blind extension study, and women without an intact uterus were allowed
to enroll in a 52-week open-label extension study.
The second clinical trial was a 12-week,
randomized, double-blind, placebo-controlled, parallel-group study that
enrolled 919 generally healthy postmenopausal women between 41 to 79 years of
age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on
a vaginal smear, a vaginal pH >5.0, and who identified either moderate to
severe vaginal dryness (dryness cohort) or moderate to severe dyspareunia
(dyspareunia cohort) as most bothersome to her at baseline. Treatment groups
included 60 mg Osphena (n=463) and placebo (n=456). Primary endpoints and study
conduct were similar to those in Trial 1.
The third clinical trial was a 52-week, randomized,
double-blind, placebo-controlled, long-term safety study that enrolled 426
generally healthy postmenopausal women between 49 to 79 years of age (mean 62
years of age) with an intact uterus. Treatment groups included 60 mg Osphena
(n=363) and placebo (n=63).
Effects on Dyspareunia
In the 1st and 2nd clinical trial, the
modified intent-to-treat population of women treated with Osphena when compared
to placebo, demonstrated a statistically significant improvement (least square
mean change from Baseline to Week 12) in the moderate to severe most bothersome
symptom (MBS) of dyspareunia (1st trial p=0.0012, 2nd trial p<0.0001).
See Table 2. A statistically
significant increase in the proportion of superficial cells and a corresponding
statistically significant decrease in the proportion of parabasal cells on a
vaginal smear was also demonstrated (p<0.0001 for both). The mean reduction
in vaginal pH between baseline and Week 12 was also statistically significant
(p<0.0001).
Table 2: Week 12 Effects on Dyspareunia (the Woman's Self-Identified
Most Bothersome Moderate to Severe Symptom of Vulvar and Vaginal Atrophy at
Baseline). Mean Change in Severity at Week 12 with Last Observation Carried
Forward (LOCF), Modified Intent-to-Treat Population*
|
|
Definitions:
LOCF = last observation carried forward; SD = standard deviation; SE =
standard error; LS = least square
|
|
*
The modified intent-to-treat population (mITT)
included only women in the ITT population who at baseline met the inclusion
criteria of ≤5 percent superficial cells
on a vaginal smear, a vaginal pH > 5.0, and who identified moderate or
severe dyspareunia as her most bothersome vaginal symptom.
|
|
1st Clinical Trial Results
|
|
|
|
Most
Bothersome Moderate to Severe Symptom at Baseline
|
Osphena
60 mg
(N=110)
|
Placebo
(N=113)
|
|
Dyspareunia
|
|
|
|
Baseline
Mean (SD)
|
2.7
(0.44)
|
2.7
(0.45)
|
|
LS Mean
Change from Baseline (SE)
|
-1.39
(0.11)
|
-0.89
(0.11)
|
|
p-value
vs. placebo
|
0.0012
|
---
|
|
2nd Clinical Trial Results
|
|
|
|
Most
Bothersome Moderate to Severe Symptom at Baseline
|
Osphena
60 mg
(N=301)
|
Placebo
(N=297)
|
|
Dyspareunia
|
|
|
|
Baseline
Mean (SD)
|
2.7
(0.47)
|
2.7
(0.47)
|
|
LS Mean
Change from Baseline (SE)
|
-1.55
(0.06)
|
-1.19
(0.07)
|
|
p-value
vs. placebo
|
<0.0001
|
---
|
16. HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Osphena tablets are white to off-white, oval,
biconvex, film coated tablets containing 60 mg of ospemifene and engraved with
"60" on one side. They are available as follows:
|
|
NDC
59630-580-90
|
Bottle
of 90 tablets
|
|
|
NDC
59630-580-30
|
Blister
pack of 30 tablets containing 2 blister cards of 15 tablets each
|
Storage and Handling
Store at 20º to 25ºC (68º to 77ºF); excursions
permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].
17. PATIENT COUNSELING INFORMATION
See FDA-approved patient 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 [see CONTRAINDICATIONS (4)].
Vaginal Bleeding
Inform postmenopausal women of the importance of
reporting unusual vaginal bleeding to their healthcare providers as soon as
possible [see Warnings and Precautions (5.2)].
Hot Flashes or Flushes
Osphena may initiate or increase the occurrence of
hot flashes in some women [see Adverse Reactions (6.1)].
Manufactured for:
Shionogi Inc.
Florham Park,NJ07932
Manufactured by:
Penn Pharmaceutical Services Ltd.
23-24 TafarnaubackIndustrial Estate
NP22 3AA,United
Kingdom
Made inUK
OSP-PI-04
Rev: 02/15
Patient Information
Osphena® (os
fee' nah)
(ospemifene)
tablets
Read this Patient Information before you start
taking Osphena and each time you get a refill. There may be new information.
This information does not take the place of talking to your healthcare provider
about your medical condition or your treatment.
What is the most important information I should
know about Osphena ?
·
Osphena is a medicine that works like estrogen in
the lining of the uterus (womb), but can work differently in other parts of the
body.
·
Taking estrogen-alone or Osphena may increase your
chance of getting cancer of the lining of the uterus (womb). Vaginal bleeding
after menopause may be a warning sign of cancer of the lining of the uterus
(womb). Your healthcare provider should check any unusual vaginal bleeding to
find out the cause. Tell your healthcare provider right away if you have any
unusual vaginal bleeding while you are taking Osphena.
·
Osphena may increase your chance of getting strokes
and blood clots.
·
You and your healthcare provider should talk
regularly about whether you still need treatment with Osphena.
What is Osphena?
Osphena is an oral prescription medicine that
contains ospemifene.
What is Osphena used for?
Osphena is used after menopause for women with or
without a uterus to:
Treat moderate to severe pain
during sexual intercourse due to changes in and around your vagina.
Who should not take Osphena?
Do not start taking Osphena if you:
have
unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning
sign of cancer of the lining of the uterus (womb). Your healthcare provider
should check any unusual vaginal bleeding to find out the cause.
currently
have or have had certain cancers
Estrogen may increase the chances of getting certain types of cancers,
such as cancer of the lining of the uterus. If you have or have had
cancer, talk with your healthcare provider about whether you should take
Osphena.currently
have or have had blood clotshad
a stroke or heart attackare
allergic to Osphena or any of its ingredients:
See the
list of ingredients in Osphena at the end of this
leaflet.think
you may be pregnant
Osphena is not for pregnant women. If you think you may be pregnant, you
should have a pregnancy test and know the results. Do not take Osphena if
the test is positive and talk to your healthcare provider.
should I tell my healthcare provider
before taking Osphena?
Before you take Osphena, tell your
healthcare provider if you:
have
any unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the
lining of the uterus (womb). Your healthcare provider should check any
unusual vaginal bleeding to find out the cause.have
any other medical conditions
Such as severe liver problems.are
going to have surgery or will be on bed rest
Your healthcare provider will let you know if you need to stop taking
Osphena.are
breast feeding
It is not known if Osphena can pass into your breast milk.
Tell your healthcare provider about
all medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements. Some medicines may affect how
Osphena works. Osphena may also affect how other medicines work. Keep a list of
your medicines and show it to your healthcare provider and pharmacist each time
you get a new medicine.
How should I take Osphena?
Take Osphena exactly how your
healthcare provider tells you to take it.Take Osphena by mouth 1 time each
day with food.You and your healthcare provider
should talk regularly (every 3 to 6 months) about the dose you are taking
and whether or not you still need treatment with Osphena.
What are the possible side effects of
Osphena?
See "What is the most important information I should know about
Osphena?"
Serious, but less common side effects
include:
strokeblood clotscancer of the lining of the uterus
(womb)
Call your healthcare provider right
away if you get any of the following warning signs or any other unusual
symptoms that concern you:
unusual vaginal bleedingchanges in vision or speechsudden new severe headachessevere pains in your chest or legs
with or without shortness of breath, weakness and fatigue
Less serious, but common side effects
include:
hot flushes or flashesvaginal dischargemuscle spasmsincreased sweating
These are not all the possible side effects of
Osphena. For more information, ask your healthcare provider or pharmacist. Tell
your healthcare provider about any side effects that bother you or does not go
away.
Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
What can I do to lower my chances of
a serious side effect with Osphena?
Talk with your healthcare provider
regularly about whether you should continue taking Osphena.If you have a uterus, talk with
your healthcare provider about whether the addition of a progestin is
right for you.See your healthcare provider right
away if you develop vaginal bleeding while taking Osphena.Have a pelvic exam, breast exam and
mammogram (breast x-ray) every year unless your healthcare provider tells
you something else.If members of your family have had
breast cancer or if you have ever had breast lumps or an abnormal
mammogram (breast x-ray), you may need to have breast exams more often.If you have high blood pressure,
high cholesterol (fat in the blood), diabetes, are overweight, or use
tobacco, you may have a higher chance of getting heart disease.Tell your healthcare provider if
you are going to have surgery or will be on bed rest.
Ask your healthcare provider for ways to lower your
chances of getting heart disease.
How should I store Osphena?
Store Osphena at room temperature
between 68°F to 77°F (20°C to 25°C).
General information about the safe
and effective use of Osphena.
Medicines are sometimes prescribed for conditions
that are not mentioned in patient information leaflets. Do not take Osphena for
conditions for which it was not prescribed. Do not give Osphena to other
people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important
information about Osphena. If you would like more information, talk with your
healthcare provider or pharmacist. You can ask your healthcare provider or
pharmacist for more information about Osphena that is written for health
professionals.
For more information, go to www.Osphena.com or call
Shionogi Inc. at 1-855-Osphena (1-855-677-4362).
What are the ingredients in Osphena?
Active Ingredient: ospemifene
Inactive ingredients: colloidal silicon dioxide,
hypromellose, lactose monohydrate, magnesium stearate, mannitol,
microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized
starch, sodium starch glycolate, titanium dioxide, and triacetin.
This Patient Information has been approved by the
U.S. Food and Drug Administration.
Manufactured for:
Shionogi Inc.
Florham Park, NJ 07932
Manufactured by:
Penn Pharmaceutical Services Ltd.
23-24 Tafarnauback Industrial Estate
Tredegar, Gwent, South Wales
NP22 3AA, United Kingdom
Made in UK
OSP-PIL-04
Revised: 02/15
PRINCIPAL DISPLAY PANEL - 60 mg
Tablet Bottle Label
NDC 59630-580-90
90 Tablets
Osphena®
(ospemifene) tablets
60 mg
For oral use only
SHIONOGI INC.
Rx only
|
Osphena ospemifene
tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:59630-580
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
OSPEMIFENE (OSPEMIFENE)
|
OSPEMIFENE
|
60 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
SILICON DIOXIDE
|
|
|
HYPROMELLOSE, UNSPECIFIED
|
|
|
LACTOSE MONOHYDRATE
|
|
|
MAGNESIUM STEARATE
|
|
|
MANNITOL
|
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
POLYETHYLENE GLYCOL, UNSPECIFIED
|
|
|
POVIDONE, UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
TRIACETIN
|
|
|
STARCH, CORN
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
|
Product Characteristics
|
|
Color
|
WHITE (white to off-white)
|
Score
|
no score
|
|
Shape
|
OVAL (oval biconvex)
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
60
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:59630-580-90
|
90 TABLET, FILM COATED in 1 BOTTLE
|
|
|
2
|
NDC:59630-580-18
|
1 BLISTER PACK in 1 PACKAGE
|
|
|
2
|
|
15 TABLET, FILM COATED in 1 BLISTER PACK
|
|
|
3
|
NDC:59630-580-55
|
1 BLISTER PACK in 1 PACKAGE
|
|
|
3
|
|
5 TABLET, FILM COATED in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA203505
|
02/26/2013
|
|
|
|
Labeler - Shionogi
Inc. (949127786)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
PENN
PHARMACEUTICAL SERVICES LTD
|
|
226277259
|
MANUFACTURE(59630-580)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Carton
Service
|
|
928861723
|
PACK(59630-580)
|
|
|
|
|
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Almac
Pharma Services LLC
|
|
078607239
|
PACK(59630-580)
|
Revised:
04/2017
Shionogi Inc.
