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Pregnancy Warning
Tamoxifen caused
fetal harm in animal studies, including abortions, premature delivery, and death. Because of the potential for serious adverse
effects to the fetus, this drug should not be used by pregnant women.
Breast-feeding
Warning
No information
is available from either human or animal studies. However, it is likely that this drug is excreted in human milk, and because
of the potential for serious adverse effects in nursing infants, you should not take this drug while nursing.
Safety Warnings For This Drug: [top]
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FDA BLACK BOX
WARNING
WARNING—For
Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer: Serious and life-threatening events associated
with NOLVADEX in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies,
stroke, and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial [a major clinical
trial involving tamoxifen1].
Uterine malignancies
[cancers] consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for NOLVADEX vs. 0.71 for
placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for NOLVADEX vs. 0.0 for placebo). For stroke,
the incidence rate per 1,000 women-years was 1.43 for NOLVADEX vs. 1.00 for placebo. For pulmonary embolism, the incidence
rate per 1,000 women-years was 0.75 for NOLVADEX vs. 0.25 for placebo.
Some of the strokes,
pulmonary emboli, and uterine malignancies were fatal.
Health care providers
should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast
cancer and women with DCIS considering NOLVADEX to reduce their risk of developing breast cancer.
The benefits of
NOLVADEX outweigh its risks in women already diagnosed with breast cancer.2 |
Facts About This Drug: [top]
Tamoxifen (NOLVADEX) was
approved by the Food and Drug Adminstration (FDA) in 1977 and is now approved to be used in several different situations
involving breast cancer.3 In 1998, the drug received approval for the reduction in breast cancer incidence
in women at high risk of developing the disease. High risk was defined as a five-year predicted risk of breast cancer of at
least 1.67 percent.
Confusion soon
erupted over whether the FDA approved tamoxifen for all women 60 years of age and older, without other risk factors for breast
cancer. The news media were initially reporting that regardless of other factors, all women 60 and older were at a five-year
predicted risk of 1.67 percent (in the high-risk category) for developing breast cancer and thus were eligible to
receive tamoxifen. This is not the case: Not all women over 60 are at a high risk of developing breast cancer and not all
women over 60 should be receiving tamoxifen to reduce the risk of breast cancer.
The large clinical
trial (over 13,000 women) that was used to gain approval for tamoxifen in reducing breast cancer incidence in high-risk women
compared tamoxifen to a placebo over a period of five years.4
The
incidence of breast cancer was reduced by 2.9 cases per year out of 1,000 women using tamoxifen. However,
there was an excess of 1.4 cases of endometrial cancer per year out of 1,000 women taking tamoxifen. {Uterine
cancer is more serious than breast cancer because it is usually diagnosed in an advanced stage--jk.} For blood clot in the
lungs, blood clot in the veins, and stroke, the number of excess cases of these serious adverse drug reactions with tamoxifen
compared to placebo was 0.5, 0.5, and 0.4 cases per year out of 1,000 women taking tamoxifen, respectively. Overall,
there was an excess of 2.8 cases of a potentially life-threatening adverse drug reaction per year out of
1,000 women on tamoxifen. Said another way, for each reduction of one case in the incidence of breast
cancer, there was about one case of a potentially life-threatening drug reaction with the use of tamoxifen.
In this study,
the benefit of tamoxifen equaled its serious
risks — it was a wash. However, there was also an increased risk of cataracts and cataract surgery in women using tamoxifen.
Side effects
In 2006 there
were three case reports of women who developed uterine sarcomas during or following treatment with tamoxifen for breast cancer.
Two of these three women died.5
Endometrial cancer,
involving the lining of the uterus, is the most common form of cancer in this organ, accounting for approximately 95 percent of
all uterine cancers. Uterine sarcoma is a rare cancer of the body of the uterus, accounting for 2 to 5 percent of all
uterine cancers. Because it is usually diagnosed at a more advanced stage than other uterine tumors, women diagnosed usually
have a poorer outcome and shorter survival than others.
Evidence of the
risk of uterine sarcoma with tamoxifen use, leading to the FDA’s decision to include a black-box warning, came in a
letter to the New England Journal of Medicine from FDA staff in June 2002.6 The FDA found that between 1978, when tamoxifen was first approved in the United
States, and April 2001, there were 43 cases of uterine sarcoma reported to the agency or published in the medical literature.
In addition, this cancer was reported to have developed in 116 women in other countries who had used tamoxifen for breast
cancer.
The Medical Letter
on Drugs and Therapeutics published a brief article reviewing information on the interaction of tamoxifen and selective serotonin
reuptake inhibitor (SSRI), a class of drugs used to treat depression. The article summarized the results of two observational
studies on the effect of SSRIs on tamoxifen and the success rate of tamoxifen in preventing recurrence of breast cancer. One
study found a higher 2-year recurrence rate and the other study found no association of a recurrence rate.7
Regulatory actions
surrounding tamoxifen
2002: In June 2002,
the FDA required a black-box warning, the strongest type of warning that the agency can require, on the professional product
label for the drug. The warning concerns increased risk of sometimes fatal uterine cancers, stroke, and blood clots in the
lungs (pulmonary embolism) in women at high risk of breast cancer who use the drug to reduce the incidence of breast cancer
and in women with a form of breast cancer called ductal carcinoma in situ (DCIS). DCIS is characterized by abnormal cells
that involve only the lining of a duct. Such cells have not yet spread outside the duct to other breast tissues. It is a noninvasive
cancer that can become invasive in some cases.
The June 2002
labeling change was aimed at women who are considering tamoxifen as a way to reduce the incidence of breast cancer or those
with DCIS for whom a survival benefit of the drug has not been demonstrated. At this time, the known benefits of tamoxifen
outweigh its risks in women already diagnosed with other kinds of breast cancer.
Before You Use This Drug: [top]
Do not use if
you have or have had:
- blood-clotting problems
- pregnancy or are breast-feeding
- stroke
- uterine malignancies
- pulmonary emboli
- deep vein thrombosis (DVT)
Tell your doctor
if you have or have had:
- allergy to tamoxifen
- blood disorder
- cataracts or other vision problems
- high cholesterol
Tell your doctor
about any other drugs you take, including aspirin, herbs, vitamins, and other nonprescription products. Ask for exams of your eyes8 and for a test to detect endometrial cancer before you start to take tamoxifen.9
When You Use This Drug: [top]
- 8See your doctor regularly for close monitoring while taking this drug.
- Continue taking this drug even if you get an upset stomach. However, check with your doctor if vomiting
occurs shortly after drug is taken.
- Take analgesics if needed for pain, which often occurs when tamoxifen is started but then subsides.
- For women: Tamoxifen may increase fertility. Do not become pregnant. Use barrier or nonhormonal contraceptives.
Tell your doctor immediately if you suspect you are pregnant.
How to Use This Drug: [top]
- If you miss a dose, take it as soon as you remember, but skip it if it is almost time for the next dose.
Do not take double doses.
- Do not share your medication with others.
- Take the drug at the same time(s) each day.
- Store at room temperature with lid on tightly. Do not store in the bathroom. Do not expose to heat, moisture,
or strong light. Keep out of reach of children.
Interactions with Other Drugs: [top]
The following
drugs, biologics (e.g., vaccines, therapeutic antibodies), or foods are listed in Evaluations of Drug Interactions 2003 as
causing “highly clinically significant” or “clinically significant” interactions when used together
with any of the drugs in this section. In some sections with multiple drugs, the interaction may have been reported for one
but not all drugs in this section, but we include the interaction because the drugs in this section are similar to one another.
We have also included potentially serious interactions listed in the drug’s FDA-approved professional package insert
or in published medical journal articles. There may be other drugs, especially those in the families of drugs listed below,
that also will react with this drug to cause severe adverse effects. Make sure to tell your doctor and pharmacist the drugs
you are taking and tell them if you are taking any of these interacting drugs:
aminoglutethimide,
AVELOX, clopidogrel, COUMADIN, CYTADREN,10 ESTRADERM, estrogen, moxifloxacin, NORVIR, PLAVIX, PREMARIN, ritonavir, warfarin.
Adverse Effects: [top]
Call your doctor
immediately if you experience:
For both women
and men:
- confusion
- blistering, peeling, or loosening of skin and mucous membranes
- blurred vision
- yellowing of skin or eyes
- shortness of breath
- swelling or pain in legs
- weakness or sleepiness
- chest pain, anxiety, cough, fainting, fast heartbeat, sudden shortness of breath, trouble breathing, dizziness
or lightheadedness
For women:
- pain or pressure in pelvis
- change in vaginal discharge
- bleeding
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Gooman & Gilman (pharmacology text
book, 2006 Edition) and other journal articles
The numbers are for Goodman &
Gilman’s The Pharmacological Basis of Therapeutics, 11th edition (2006), which I bought--a balanced source
for information.
Estrogen increases the risk of endometrial
cancer about 5 fold (thus the use of a prostaglandin). (1552).
Loss of tissue lining the vagina or bladder
leads to a variety of symptoms in many postmenopausal women. These include dryness
and itching of the vagina, dyspareunia, swelling of tissue in the genital region, pain during urination, a need to urinate
urgently or ofte3n, and sudden or unexpected urinary incontinence. (1553)
Gallbladder disease 2-3 fold.
Breast cancer through (a) stimulating
the growth rate of such cancer, (b) increase breast cell proliferation including those with mutations, (c) possible directly
through the production of a reactive chemical (4-hydroxycatechol) from the production of catechol estrogens. (1553).
Estrogens produce a favorable lipoprotein
profile, promote vasodilatation, inhibit the response to vascular injury, and reduce atherosclerosis. These effects should produce a reduction in cardiovascular disease in postmenopausal women; who ever in
a couple of clinical trials this was not substantiated. It is not clear if similar
results would occur with different drugs/dose in different patient populations. (1553)
The
Women’s Health Initiative also demonstrated that conjugated estrogen in combination with a progestin reduces the risk
of colon cancer by roughly one-half in postmenopausal women. (1554). As I commented
on my website, this more than makes up for the increased risk of breast cancer.
Osteoporosis: The primary mechanism by which estrogens act is to decrease bone
resorption; consequently, estrogens are more effective at preventing rather than restoring bone loss. Estrogens are most effective if treatment is initiated before significant bone loss occurs, and their maximal
beneficial effects require continuous use; bone loss continues if treatment is discontinued. (1553).
About 1980, epidemiological studies indicated
that this treatment increased the incidence of endometrial carcinoma. This led
to the use of HRT that includes a progestin to limit estrogen-related hyperplasia.
(1555).
Cardiovascular Disease: The incidence
of cardiovascular disease is low in premenopausal women, rising rapidly after menopause, and epidemiological studies consistently
showed an association between estrogen use and reduced cardiovascular disease in postmenopausal women (1553).
Postmenopausal Hormone Use and Primary Prevention of Heart Disease
and Stroke in Healthy Women
19 December 2000 | Volume 133 Issue 12 | Page S60
Summary on the web at http://www.annals.org/cgi/content/summary/133/12/933
The researchers studied 70,533 postmenopausal female nurses who
had no known history of previous cardiovascular disease.
Starting in 1978, the researchers began collecting information on
the type of hormones taken and, starting in 1980, on the dose of estrogen. Further follow-up surveys continued
to update information on hormone use and asked whether the women had had a heart attack or stroke. The
researchers confirmed all reported events, including deaths, by examining medical records and death certificates.
Women who took hormones were 40% less likely to have a heart attack
than those who never used hormones. The risk was reduced by about the same amount regardless of whether women had
taken high or low doses of estrogen. No difference in the risk for stroke was found between hormone
users and nonusers. However, women who took 0.625 mg or more of oral conjugated estrogen per day (an
average dose) and those who took estrogen with a progestin hormone had a higher risk for stroke than women who
never used hormones. Overall, women who had used postmenopausal hormones were about 23% less likely to have
a heart attack or stroke than women who had never taken them.
The Journal of Clinical Endocrinology
& Metabolism Vol. 87, No. 4 1509-1516.
Differential Effects of Oral Estrogen versus Oral Estrogen-Androgen
Replacement Therapy on Body Composition in Postmenopausal Women
Adrian S. Dobs, Tam Nguyen, Cindy Pace and Carla P. Roberts
Copyright © 2002 by The Endocrine Society.
Estrogen-androgen (E/A) therapy is also used
for vasomotor symptom relief and has been shown to increase lean body mass while decreasing fat mass. After E/A treatment, there were statistically significant increases in lean body mass
by 1.232 kg. When subjects were given self-reporting questionnaires,
more improvement was noted in sexual functioning and quality of life in the E/A group when compared
with patients receiving E alone. There were no noteworthy side effects. When subjects were given
self-reporting questionnaires, more improvement was noted in sexual functioning and quality of life in the
E/A group when compared with patients receiving E alone. There were no noteworthy side effects.
In conclusion, E/A replacement therapy can improve body composition, lower-body muscle strength, quality
of life, and sexual functioning in postmenopausal women.
J Reprod Med. 1998 Oct;43(10):847-56
Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual
behavior and neuroendocrine responses.
RESULTS: Estrogen-androgen
therapy significantly improved sexual sensation and desire after four and eight weeks of double-blind treatment in comparison
to previous estrogen therapy and postplacebo baseline assessments.
CONCLUSION: Sexual
desire, satisfaction and frequency in postmenopausal women taking hormonal therapy were improved significantly by combined
estrogen-androgen therapy but not by estrogen or estrogen-progestin therapy.
Journal of the National
Cancer Institute, Vol. 92, No. 4, 328-332, February
16, 2000
© 2000 Oxford University Press
Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin
{Estrogen alone 6% higher, estrogen + prosgestin 24% higher}
BACKGROUND: Hormone replacement therapy
(HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United
States in the 1960s and 1970s. Recent prescribing practices have favored combination
HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement
therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist
on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of
developing breast cancer in a population-based, case-control study. METHODS: Case subjects included
those with incident breast cancers diagnosed over 4 years
in Los Angeles County, CA, in the late 1980s and 1990s.
Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case
subjects and control subjects were interviewed in person to collect information on known breast cancer risk
factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal
control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer
risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously
for the different forms of HRT and for known risk factors of breast cancer. All P values are
two-sided.
RESULTS: HRT was associated with a
10% higher breast cancer risk for each 5 years of use (OR5 = 1.10; 95% confidence interval [CI] = 1.02-1.18).
Risk was substantially higher for CHRT use (OR5 = 1.24; 95% CI = 1.07-1.45) than for ERT
use (OR5 = 1.06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR5 = 1.38; 95%
CI = 1.13-1.68) than for CCRT (OR5 = 1.09; 95% CI = 0.88-1.35), but this difference was not
statistically significant. Conclusions: This study provides strong evidence that the addition of a progestin
to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have
important implications for the risk-benefit equation for HRT in women using CHRT.
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