Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
Climara Pro is contraindicated in women
with any of the
following conditions:
Undiagnosed abnormal genital bleeding [see Warnings
and Precautions
(5.2)]
Breast cancer or history of
breast cancer [see Warnings
and Precautions (5.2)]
Estrogen-dependent neoplasia [see Warnings and
Precautions (5.2)]
Active DVT, PE or a
history of these conditions [see Warnings and Precautions (5.1)]
Active arterial thromboembolic
disease (for example,
stroke or MI),
or
a history of these conditions
[ see Warnings and Precautions
(5.1)]
Known
anaphylactic reaction, or angioedema, or hypersensitivity to Climara Pro
Hepatic impairment or diseaseProtein C, protein
S, or antithrombin
deficiency, or other thrombophilic disorders
5
Warnings and Precautions
5.1 Cardiovascular Disorders
Extensive changes to table; please refer to label
5.2 Malignant Neoplasms
Additions and/or revisions underlined:
Breast Cancer
After a mean
follow-up of 5.6 years, the
WHI substudy of daily
CE (0.625 mg) plus MPA
(2.5 mg) reported an increased risk of invasive
breast cancer in women
who
took daily CE plus
MPA compared to
placebo.
In
this substudy, prior use
of
estrogen-alone or estrogen plus progestin therapy
was reported
by 26 percent of the women. The
relative risk of invasive
breast cancer was
1.24, and the absolute risk
was 41 versus 33 cases
per
10,000 women- years,
for
CE plus MPA compared
with placebo. Among women who
reported prior use
of hormone therapy, the relative
risk of invasive
breast cancer was 1.86, and
the absolute risk was 46
versus 25 cases per 10,000
women-years, for CE plus MPA
compared with placebo. Among women who reported
no prior use of hormone therapy, the relative
risk of invasive breast cancer
was 1.09, and the absolute risk
was 40 versus 36 cases per 10,000 women-years for CE plus
MPA compared with placebo. In the
same substudy, invasive breast cancers
were larger, were more
likely to be node positive,
and were diagnosed at a
more advanced stage in the CE (0.625
mg) plus MPA (2.5 mg) group
compared with the placebo group. Metastatic disease was rare with
no apparent difference between
the two groups. Other prognostic factors such as histologic subtype, grade
and hormone receptor status did not differ between the groups5 [see Clinical
Studies (14.5)].
The WHI substudy of daily CE (0.625
mg)-alone provided information about breast cancer in
estrogen-alone users.
In the WHI estrogen-alone substudy,
after an average
follow-up of 7.1
years, daily CE-alone was
not
associated with an increased risk of invasive breast cancer [relative
risk (RR) 0.80] 6 [see
Clinical Studies (14.5)].
Consistent with the WHI clinical
trials, observational studies have also reported an increased
risk of breast cancer with estrogen plus
progestin therapy, and a smaller
increase in the
risk for breast cancer with estrogen-alone therapy,
after several years
of
use. The risk increased
with duration of use, and appeared to return to baseline over about 5
years after stopping treatment (only
the observational studies have
substantial data on risk
after stopping). Observational studies also suggest
that the risk of breast cancer was greater,
and became apparent
earlier, with estrogen
plus progestin therapy as compared to estrogen-alone therapy.
These studies have not
generally found
significant variation in the risk
of breast cancer among different estrogen
plus progestin combinations,
doses, or routes of administration. The use of estrogen-alone
and estrogen plus progestin
has been reported
to result in an increase
in abnormal mammograms
requiring further evaluation.
All women should
receive yearly breast examinations by a healthcare provider
and perform monthly breast self- examinations.
In addition, mammography
examinations should be scheduled based on patient age, risk factors, and
prior mammogram results.
Endometrial Cancer
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 nonusers, and appears
dependent on duration of treatment
and on estrogen dose. Most studies show
no significant increased
risk associated with use
of estrogens for less than 1 year.
The greatest risk appears 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.
Clinical
surveillance of all women
using estrogen-alone or estrogen plus
progestogen therapy is
important. Perform adequate diagnostic
measures, including directed or random endometrial sampling when indicated,
to rule
out malignancy in postmenopausal women with
undiagnosed persistent or recurring abnormal genital bleeding
with unknown etiology.
There is
no evidence that the
use of natural estrogens results in a different
endometrial risk
profile than synthetic estrogens of equivalent estrogen dose.
Adding a progestogen
to estrogen therapy in postmenopausal women
has been shown to reduce
the risk of endometrial hyperplasia,
which may be a precursor
to endometrial cancer.
Ovarian Cancer
The CE plus MPA substudy of WHI reported that estrogen
plus progestin increased the risk of ovarian cancer.
After an average
follow-up of 5.6 years, the relative risk for ovarian
cancer for CE plus MPA
versus placebo was 1.58 (95 percent CI,
0.77-3.24), but it was not statistically significant. The
absolute risk for CE plus
MPA versus placebo was
4 versus
3 cases
per 10,000 women-years.7
5.13 Hypocalcemia
Additions and/or revisions underlined:
Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the
benefits of estrogen
therapy, including
Climara Pro, outweigh the
risks in such women.
5.15 Hereditary Angioedema
Additions and/or revisions underlined: Exogenous
estrogens may
exacerbate symptoms
of angioedema in
women with hereditary angioedema. Consider whether the benefits of estrogen therapy,
including
Climara Pro, outweigh the risks
in such women.
5.16
Exacerbation of Other Conditions
Additions and/or revisions underlined:
Estrogen
therapy, including Climara Pro, may
cause an exacerbation of asthma, diabetes mellitus,
epilepsy, migraine, porphyria,
systemic lupus erythematosus, and hepatic hemangiomas.
Consider whether the
benefits of estrogen
therapy outweigh
the risks in women with
these conditions.
5.17 Laboratory Tests
Additions and/or revisions
underlined:
Serum follicle
stimulating hormone
(FSH) and
estradiol levels have not been
shown to be useful in the management of postmenopausal women with
moderate to severe
vasomotor symptoms.
5.5 Hypercalcemia
Additions and/or revisions underlined:
Estrogen administration
may lead
to severe hypercalcemia
in women with breast cancer and bone metastases. Discontinue estrogens,
including Climara Pro if
hypercalcemia occurs, and
take appropriate measures to reduce the
serum calcium level.
5.6
Visual Abnormalities
Additions and/or revisions underlined:
Retinal vascular thrombosis has been
reported in women receiving estrogens.
Discontinue Climara Pro
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
Climara Pro, if examination reveals papilledema or retinal
vascular lesions.
5.7
Addition of a Progestogen When a
Woman Has Not Had a Hysterectomy
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.
There are, however, possible risks that may be
associated with the use of progestogens with estrogens compared to estrogen-alone regimens.
These include an increased risk of breast cancer.
5.9
Exacerbation of Hypertriglyceridemia
Additions and/or revisions underlined:
In women with
pre-existing hypertriglyceridemia, estrogen
therapy may be associated with elevations of plasma
triglycerides leading
to pancreatitis. Discontinue Climara Pro if pancreatitis occurs.
5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice
Additions and/or revisions underlined:
Estrogens
may be poorly metabolized in women
with hepatic impairment.
Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use
or with
pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Climara Pro.
5.11
Exacerbation of Hypothyroidism
Additions and/or revisions underlined:
Estrogen administration
leads to increased thyroid-binding
globulin (TBG) levels.
Women with normal thyroid
function can compensate for the increased TBG by making
more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women
dependent on thyroid hormone replacement therapy
who are also receiving estrogens may require increased
doses of their thyroid replacement therapy.
Monitor thyroid
function in these women during
treatment with Climara Pro
to maintain their free
thyroid hormone levels in an
acceptable range.
5.12 Fluid Retention
Additions and/or revisions underlined:
Estrogens plus
progestogens may cause
some degree of fluid retention. Monitor any woman
with a condition(s) that might predispose her to fluid retention,
such as a cardiac or renal impairment. Discontinue estrogens plus
progestogens therapy,
including Climara
Pro, with evidence of medically
concerning fluid retention.
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Climara
Pro
is not indicated
for use in pregnancy. There are
no data with the use of Climara
Pro 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 (estrogens and progestins) before
conception or during early
pregnancy.
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:
Risk Summary
Estrogens plus
progestogens are present in
human milk and can reduce milk production in breast-feeding women. This reduction
can occur at any
time but is less likely to occur once
breast-feeding is well-established.
The developmental and health benefits
of
breastfeeding should be
considered along
with the mother’s
clinical need for Climara Pro
and any potential adverse effects
on
the breastfed child from Climara
Pro or from the underlying maternal condition.
8.4 Pediatric Use
Additions and/or revisions underlined:
Climara Pro is not indicated for use in pediatric
patients. Clinical studies
have not been conducted
in the pediatric
population.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Advise women to read the FDA-approved
patient labeling (Patient Information
and Instructions for Use
Vaginal Bleeding
Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as
possible [see Warning
and Precautions (5.2)].
Possible Serious Adverse
Reactions with Estrogen Plus Progestogen Therapy
Inform postmenopausal women of possible
serious adverse
reactions of estrogen
plus progestogen therapy
including Cardiovascular Disorders, Malignant Neoplasms,
and
Probable Dementia [see Warning and Precautions (5.1,
5.2, 5.3)].
Possible Common
Adverse Reactions with Estrogen plus Progestogen Therapy
Inform postmenopausal women of possible
less serious but common adverse
reactions of estrogen
plus progestogen therapy such as
headache, breast pain and tenderness,
nausea and vomiting.
Patient Information Climara Pro
Extensive changes; please refer to label
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