Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
Divigel
is contraindicated in women with any of the following conditions:
5
Warnings and Precautions
5.1 Cardiovascular Disorders
Additions
and/or revisions underlined:
Divigel
is contraindicated in women with active DVT, PE, stroke, or a history of these
conditions [see Contraindications (4)]. Immediately discontinue Divigel if a PE, DVT, or
stroke occurs or is suspected.
The
safety and efficacy of Divigel for the prevention of cardiovascular disorders has
not been established.
The
Women’s Health Initiate (WHI) estrogen-alone trial reported increased risks of
pulmonary embolism (PE), deep vein thrombosis (DVT), and stroke, in postmenopausal
women (50 to 79 years of age, average age 63.4 years) during 7.2 years of treatment
with daily oral conjugated estrogen (CE) [0.625 mg] relative to placebo.
Analyses were also conducted in women aged 50-59 years, a group of women more
likely to present with onset of moderate to severe VMS compared to women of
other age groups in the trial.
Only
daily oral 0.625 mg CE was studied in the WHI estrogen-alone trial. Therefore,
the relevance of the WHI findings regarding adverse cardiovascular events to
lower CE doses, other routes of administration, or other estrogen products is
not known. Without such data, it is not possible to definitively exclude these risks
or determine the extent of these risks for other products [see Clinical Studies (14.2)].
Venous
Thromboembolism
In
women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk
for PE of 1.53 (95% confidence interval [CI], 0.63, 3.75) for CE compared to placebo,
with an absolute risk difference of 4 per 10,000 women-years (WYs; 10 versus 6).
The relative risk for DVT was 1.66 (95% CI 0.75, 3.67) for CE compared to
placebo, with a risk difference of 5 per 10,000 WYs (13 versus 8).
In
the overall study population of women aged 50-79 years, the WHI estrogen-alone
trial reported a relative risk of PE of 1.35 (95% CI 0.89, 2.05) for CE compared
to placebo, with a risk difference of 4 per 10,000 WYs (14 versus 10). The relative
risk for DVT was
1.48
(95% 1.06, 2.07) for CE compared to placebo, with a risk difference of 7 per 10,000
WYs (23 versus 15) [see Clinical Studies(14.2)].
Stroke
In
women aged 50-59 years, the WHI estrogen-alone trial reported a relative risk for
stroke of 0.99 (95% 0.53, 1.85) for CE compared to placebo, with a risk
difference of -1 per 10,000 WYs (16 versus 17).
In the overall study
population of women aged 50-79 years, the WHI estrogen-alone trial reported a relative
risk for stroke of 1.35 (95%, 1.07, 1.70) for CE compared to placebo, with a
risk difference of 11 per 10,000 WYs (45 versus 34) [see Clinical Studies
5.2 Malignant Neoplasms
Additions
and/or revisions underlined:
Endometrial
Cancer
In
Divigel-treated menopausal women with a uterus with persistent or recurring
abnormal genital bleeding of unknown etiology, perform adequate diagnostic measures,
including directed or random endometrial sampling when indicated, to assess for
endometrial cancer.
…
Adding
a progestogen to estrogen-alone therapy has been shown to reduce the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer. There are,
however, possible risks associated with the use of progestogens plus estrogens that
differ from those of estrogen-alone regimens [see Warnings and Precautions (5.3)].
Breast
Cancer
Surveillance
measures for breast cancer, such as breast examinations and mammography, are recommended.
The use of estrogen-alone therapy has been reported to result in an increase in
abnormal mammograms requiring further evaluation.
In the WHI estrogen-alone trial, after an average
follow-up of 7.1 years, daily CE-alone was not associated with an increased risk
of invasive breast cancer. Among women 50-59 years old, the relative risk
was 0.82 (95% CI, 0.50, 1.34) for CE compared to placebo, with a risk
difference of -5 per 10,000 WYs (24 versus 29). In the overall study population
of women aged 50-79 years (average age 63.4 years), the relative risk was 0.79
(95% CI, 0.61, 1.02), with a risk difference of -7 per 10,000 WYs (28 versus
35). [see Clinical Studies (14.2)]. However,
a large meta-analysis including 24 prospective studies of postmenopausal women comparing
current use of estrogen-only products with use duration of 5 to 14 years (average
of 9 years) versus never use reported a relative risk for breast cancer of 1.33
(95% CI, 1.28 to 1.38).1
Ovarian
Cancer
A
large meta-analysis including 17 prospective studies of postmenopausal women
compared current use of estrogen-only products versus never use and reported a relative
risk for ovarian cancer of 1.37 (95% CI, 1.26 to 1.50). The duration of hormone
therapy use that was associated with an increased risk of ovarian cancer is
unknown.2
5.3 Risks Associated with the Co-administration of Estrogen Plus Progestogen
Additions and/or
revisions underlined:
Studies
of the addition of a progestogen for 10 or more days of a cycle of estrogen
administration, or daily with estrogen in a continuous regimen, have reported a
lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment
alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
If
Divigel is administered with a progestogen, there are possible risks associated
with the use of progestogens plus estrogens that differ from those of
estrogen-alone regimens. Refer to prescribing information for progestogens
indicated for the prevention of endometrial hyperplasia in non-hysterectomized women receiving
estrogens.
8
Use in Specific Populations
8.5 Geriatric Use
Additions
and/or revisions underlined:
…
Since
the trial was conducted in women 65 to 79 years of age, it is unknown whether
these findings apply to younger postmenopausal women [see Clinical Studies (14.3)]. The safety
and efficacy of Divigel for the prevention of dementia has not been
established.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Visual Abnormalities
Additions and/or
revisions underlined:
Retinal vascular thrombosis has been reported in
patients receiving estrogens. Discontinue Divigel pending examination if there
is sudden partial or complete loss of vision, or a sudden onset of proptosis,
diplopia, or migraine. Permanently discontinue estrogens, including
Divigel, if examination reveals papilledema or retinal vascular lesions.
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
…
In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4%
and 15% to 20%, respectively.
8.2 Lactation
Additions and/or revisions underlined:
…
The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for
Divigel and any potential adverse effects on
the breastfed child from Divigel or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Unintentional
Secondary Exposure to Divigel
Inform
women about the possibility of secondary exposure to Divigel:
Apply Divigel as directed and keep children from
contacting exposed application site(s). If direct contact with the application
site occurs, wash the contact area thoroughly with soap and water.
Look for signs of unexpected sexual development, such
as breast mass or increased breast size in prepubertal children.
If signs of unintentional secondary exposure are
noticed:
Pets may also be unintentionally exposed to Divigel if
above precautions are not followed.
…
PATIENT
INFORMATION
Additions and/or revisions underlined:
…
Who
should not use Divigel?
Do
not start using Divigel if you:
Vaginal bleeding
after menopause may be a warning sign of cancer of the uterus (womb). Your
healthcare provider should check any unusual vaginal bleeding to find out the
cause.
…
What
should I do if someone else is exposed to Divigel?
To reduce the chance of transfer to another person (or
pet) let the Divigel dry completely. Wash your hands with soap
and water after application. If someone else is exposed to Divigel by
direct contact with the wet gel, have that person wash the area of
contact with soap and water right away. This is especially important for
men and children. The longer the gel is in contact with the skin before washing,
the greater the chance that the other person (or pet) will absorb
some of the estrogen hormone. This may harm them. In case of any signs or
symptoms of estrogen exposure in the other person (or pet), contact your
healthcare provider (or veterinarian, if appropriate).
…
Call
your healthcare provider right away if you get any of the following warning
signs or any other unusual symptoms that concern you:
…
…
You may report side effects to FDA at 1-800-FDA-1088
or Vertical Pharmaceuticals, LLC at 1-800-444-5164.
…
Approved Drug Label (PDF)
Boxed Warning
(additions
underlined)
…
![]()
Only daily oral
0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore,
the relevance of the WHI findings regarding adverse cardiovascular events and
dementia to lower CE doses, other routes of administration, or other
estrogen-alone products is not known. Without such data, it is not possible to
definitively exclude these risks or determine the extent of these risks for
other products. Discuss with your patient the benefits and risks of
estrogen-alone therapy, taking into account her individual risk profile.
...
![]()
Only daily oral
0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy
of the WHI. Therefore, the relevance of the WHI findings regarding adverse
cardiovascular events, dementia and breast cancer to lower CE plus other MPA
doses, other
routes of administration, or other estrogen plus progestin products is not
known. Without such data, it is not possible to definitively exclude these
risks or determine the extent of these risks for other products. Discuss with
your patient the benefits and risks of estrogen plus progestin therapy, taking
into account her individual risk profile.
…
4
Contraindications
(addition underlined)
…
…
8
Use in Specific Populations
8.1 Pregnancy
(additions
underlined)
… Animal studies to evaluate embryo/fetal toxicity were not conducted with
Divigel.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Possible
Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy
Inform
postmenopausal women of possible less serious but common adverse reactions of
estrogen-alone therapy such as headaches, breast pain and
tenderness, nausea and vomiting.
PATIENT INFORMATION
(additions
and/or revisions underlined)
…
WHAT
IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Divigel (AN ESTROGEN
HORMONE)?
…
Only one estrogen-alone product and dose has been
shown to increase your chances of getting strokes, blood clots, and dementia.
Only one estrogen with progestin product and dose has been shown to increase
your chances of getting heart attacks, strokes, breast cancer, blood clots, and
dementia.
Because other products and doses have
not been studied in the same way, it is not known how the use of Divigel will
affect your chances of these conditions. You and your healthcare provider
should talk regularly about whether you still need treatment with Divigel.
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(addition underlined)
…
Divigel was studied at doses
of 0.25, 0.5 and 1.0 gram per day in a 12-week, double-blind,
placebo-controlled study that included a total of 495 postmenopausal women
(86.5 percent Caucasian). The adverse events that occurred at a rate greater
than 5 percent and greater than placebo in any of the treatment groups
are summarized in Table 1.
(please refer to label to
view Table 1)
…
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion)
Risk Summary
Divigel is not indicated for use in pregnancy. There are
no data with the use of Divigel in pregnant women; however, epidemiologic
studies and meta-analyses have not found an increased risk of genital or
nongenital birth defects (including cardiac anomalies and limb-reduction
defects) following exposure to combined hormonal contraceptives (estrogen and
progestins) before conception or during early pregnancy.
8.2 Lactation
(PLLR
conversion)
Risk Summary
Divigel is not indicated for
use in females of reproductive potential. Estrogens are present in human milk
and can reduce milk production in breast-feeding females. This reduction can
occur at any time but is less likely to occur once breast-feeding is well- established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Possible Less Serious but More Common Adverse
Reactions with Estrogen-Alone Therapy
Inform postmenopausal women of possible less serious but
common adverse reactions of estrogen-alone therapy such as metrorrhagia,
breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory
infection.
…
PATIENT INFORMATION
(additions
underlined)
…
What
are the possible side effects of Divigel?
Side
effects are grouped by how serious they are and how often they happen when you
are treated. Serious, but less common side effects include:
…
Low blood calcium (hypocalcemia)
Fluid retention
…
Low thyroid levels in your blood
…
High triglyceride (fat) levels in your
blood
High blood calcium (hypercalcemia)
Worsening of angioedema (swelling of
face and tongue)
Changes in certain laboratory test
results
…
The
most common side effects of Divigel include:
Irregular
vaginal bleeding or spotting
Breast
tenderness
Vaginal
yeast infection
Cold
Upper
respiratory tract (nose, sinuses, pharynx or larynx) infection
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Malignant Neoplasms
Ovarian Cancer
Additions
and/or revisions underlined:
… A meta-analysis
of 17 prospective
and 35 retrospective epidemiology studies
found that women who
used hormonal therapy for menopausal symptoms
had an increased risk for ovarian cancer. The primary analysis,
using case-control
comparisons, included
12,110 cancer cases
from
the 17 prospective studies.
The
relative risks associated with current use
of hormonal
therapy was
1.41 (95% confidence interval [CI] 1.32
to 1.50); there was no difference in
the risk estimates
by duration
of the exposure (less
than 5 years [median
of 3 years] vs. greater than
5 years
[median of 10 years] of use before the cancer diagnosis). The relative risk
associated
with combined current and
recent use
(discontinued use within 5
years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48),
and the elevated risk
was
significant for both
estrogen-alone
and estrogen plus progestin products. The exact
duration of hormone therapy use associated with
an increased risk
of ovarian cancer,
however,
is unknown.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
What are the possible side effects
of Divigel?
Additions and/or revisions underlined:
These are not all the possible side
effects of Divigel. For more information, ask your healthcare provider or
pharmacist for advice about side effects. You may report side effects to Vertical Pharmaceuticals, LLC at 1-877-95-VERTI (1-877-958-3784) or
to FDA at 1-800-FDA-1088.
Keep Divigel out of the reach of
children.
… You can get more information by calling
the toll free number Customer Service: 1-866-600-4799.
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