Canada - English - Health Canada
10 and 20 mg Tablets
sanofi-aventis Canada Inc.
Date of Preparation:
2150 St. Elzear Blvd. West
May 31, 2006
Laval, Quebec H7L 4A8
Submission Control No. 106131
s-a Version 1.0 dated
NAME OF DRUG
tamoxifen citrate tablets 10 mg and 20 mg
Antineoplastic (non-steroidal antiestrogen)
AMOXIFEN THERAPY WAS ASSOCIATED WITH SERIOUS AND LIFE
THREATENING EVENTS INCLUDING UTERINE
AND DEEP VEIN THROMBOSIS IN THE
BREAST CANCER PREVENTION TRIAL
HE USE OF
TAMOXIFEN FOR BREAST CANCER PREVENTION IS NOT AN APPROVED INDICATION IN
FOLLOWING RISKS ASSOCIATED WITH TAMOXIFEN THERAPY HAVE BEEN ESTIMATED FROM THE
BREAST CANCER PREVENTION TRIAL
HE RELATIVE RISK OF TAMOXIFEN COMPARED TO PLACEBO WAS
FOR ENDOMETRIAL CANCER
FOR UTERINE SARCOMAS
FOR DEEP VEIN THROMBOSIS
HESE EVENTS WERE FATAL IN SOME PATIENTS
CARE PROVIDERS SHOULD BE AWARE OF THE POSSIBLE RISKS ASSOCIATED WITH TAMOXIFEN THERAPY AND
SHOULD DISCUSS THEM WITH THEIR PATIENTS
HE BENEFITS OF TAMOXIFEN THERAPY OUTWEIGH THE RISKS IN THE MAJORITY OF WOMEN BEING TREATED
ACCORDING TO THE APPROVED
ANADIAN INDICATION FOR THE TREATMENT OF BREAST CANCER
ACTIONS AND CLINICAL PHARMACOLOGY
Tamoxifen is a nonsteroidal agent which has demonstrated potent antiestrogenic properties in
animal test systems. The antiestrogenic effects are related to is ability to compete with estrogen
for binding sites in target tissues such as breast and uterus. Tamoxifen inhibits the induction of rat
mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of
already established DMBA-induced tumors. In this rat model tamoxifen appears to exert its
antitumor effects by binding to estrogen receptors.
In cytosols derived from human endometrium and human breast and uterine adenocarcinomas
tamoxifen competes with estradiol for estrogen receptor protein.
Reports of advanced breast cancer trials conducted world-wide, however, indicate that, using
established criteria, there is an objective response rate (complete and partial remission) to
tamoxifen of approximately 10% in patients with estrogen receptor negative tumors which may
indicate other mechanisms of action. A further small percentage of patients show positive benefit
in that they are reported to have disease stabilization. This may be explained by the shortcomings
of the assay procedure or by actions of tamoxifen at loci other than the estrogen receptor.
Ranges as large as 0 - 300 fmoL/mg protein have been reported in histologically comparable
portions of the same tumor. In addition, the collection, transport and storage of tumor specimens
can affect the validity of current estrogen receptor assays. See the TOXICOLOGY section for
details of the ESTROGEN RECEPTOR ASSAY.
The apparent discrepancy in correlation between estrogen receptor status and clinical response
may also be explained by recent in vitro evidence indicating that not all of the growth inhibiting
effects of tamoxifen are mediated through the estrogen receptor. Tamoxifen has been shown to
have a low affinity for the androgen receptor and on a binding site distinct from the estrogen
receptor. The possibility also exists that tamoxifen interferes with the action of hormonal steroids
on cell growth, that it could modulate the action of peptide hormones at their receptors by effects
on cell membranes, and that it inhibits prostaglandin synthetase thereby having the potential to limit
It is recognized that tamoxifen also displays estrogenic-like effects on several body systems
including the endometrium, bone and blood lipids.
TAMOFEN (tamoxifen citrate) is indicated for the adjuvant treatment of early breast cancer in
women with estrogen receptor positive tumors. TAMOFEN is indicated for the treatment of women
with hormone responsive locally advanced/metastatic breast cancer.
When used in the prevention setting (an indication not approved in Canada), tamoxifen is
contraindicated in patients with a history of stroke, deep venous thrombosis or pulmonary
embolism, and in patients who are at an increased risk of developing endometrial cancer.
Tamoxifen is not indicated for the prevention of breast cancer in Canada.
Tamoxifen must not be given during pregnancy. There have been a small number of reports of
spontaneous abortions, birth defects and fetal deaths after women have taken tamoxifen, although
no causal relationship has been established.
Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.
In rodent models of fetal reproductive tract development, tamoxifen was associated with changes
similar to those caused by estradiol, ethynylestradiol, clomiphene and diethylstilboestrol (DES).
Although the clinical relevance of these changes is unknown, some of them, especially vaginal
adenosis, are similar to those seen in young women who were exposed to DES in utero and who
have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small
number of pregnant women have been exposed to tamoxifen. Such exposure has not been
reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in
young women exposed in utero to tamoxifen.
Women should be advised not to become pregnant while taking tamoxifen and should use barrier
or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be
carefully examined before treatment to exclude the possibility of pregnancy. Women should be
appraised of the potential risks to the fetus, should they become pregnant while taking tamoxifen
or within two months of cessation of therapy.
Tamoxifen is contraindicated in patients with hypersensitivity to tamoxifen or any of its components.
An increased incidence of uterine malignancies has been reported in association with tamoxifen
treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect
of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as
adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed
Mullerian tumours, have also been reported. Uterine sarcoma is generally associated with a higher
FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been
reported to occur more frequently among long-term users (
2 years) of tamoxifen than non-users.
There is evidence of an increased incidence of thromboembolic events, including deep vein
thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is co-administered
with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For
treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in
women with a history of thromboembolic events.
An increased risk of stroke has been found to be associated with tamoxifen therapy in high-risk
patients being treated for the prevention of breast cancer. The use of tamoxifen for the prevention
of breast cancer is not an approved indication in Canada.
Incidence rates for the above events were estimated from a long-term clinical study called the
National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention (NSABP P-1) Trial.
In this trial, high-risk patients were randomized to either tamoxifen therapy or placebo, for the
prevention of breast cancer. Uterine malignancies were separated into cases of endometrial
adenocarcinomas and uterine sarcomas. The relative risk of tamoxifen compared to placebo was
3.1 for endometrial cancer, 4.0 for uterine sarcomas, 1.6 for stroke, 3.0 for pulmonary embolism,
and 1.6 for deep vein thrombosis.
In rats, tamoxifen can induce preneoplastic and neoplastic changes of the liver including
hepatocellular carcinomas when administered at high doses for prolonged periods. In that species
tamoxifen behaves as a partial agonist whereas it is primarily an antiestrogen in humans. For this
reason and considering the high dosage used in the rat studies (up to 100 times the normal human
therapeutic dose), the relevance of these findings to human use in unknown.
Hepatocellular carcinomas have been reported in a 2 year oncogenicity study in rats receiving
tamoxifen. In addition, gonadal tumors have been reported in mice receiving tamoxifen in long-term
studies. The clinical relevance of these cancer findings has not been established.
Cataracts were also reported in the 2 year oncogenicity study in rats, and since then it has been
established that treatment with tamoxifen has been associated with an increased incidence of
A number of second primary tumors, occurring at sites other than the endometrium and the
opposite breast, have been reported in clinical trials, following the treatment of breast cancer
patients with tamoxifen. No causal link has been established and the clinical significance of these
observations remains unclear.
TAMOFEN (tamoxifen citrate) should be used only for the conditions listed under the Indications
Use TAMOFEN (tamoxifen) cautiously in patients with existing thrombocytopenia or leukopenia.
Transient decreases in platelet counts usually to 50,000-100,000/mm
, have been observed
occasionally during treatment. However, no hemorrhagic tendency was reported and platelet counts
returned to normal even though treatment was continued.
Transient decreases in leukocytes also have been observed occasionally during treatment.
Although it was uncertain that these incidences of leukopenia and thrombocytopenia were due to
As with other additive hormonal therapy (estrogens and androgens) hypercalcemia has been
reported in some breast cancer patients with bone metastases within a few weeks of starting
treatment with tamoxifen. Patient who have metastatic bone disease should have periodic serum
calcium determinations during the first few weeks of TAMOFEN therapy and any symptoms
suggestive of hypercalcemia should be evaluated promptly. If hypercalcemia is present, appropriate
measures should be taken, and, if severe, TAMOFEN should be discontinued.
The first patient follow-up should be done within one month following initiation of treatment.
Thereafter, examinations may be performed at one to two month intervals. If adverse reactions such
as hot flushes, nausea or vomiting occur, and are severe, they may be controlled in some patients
by a dosage reduction without loss of effect on the disease.
Bone pain, if it should occur, may require analgesics.
Any patients receiving tamoxifen or having previously received tamoxifen who report abnormal
vaginal bleeding should be promptly investigated.
In clinical studies, the median duration of treatment before the onset of a definite objective response
has been two months. However, approximately 25% of patients who eventually responded were
treated for four or more months before a definite objective response was recorded.
The duration of TAMOFEN treatment will depend on the patient's response. The drug should be
continued as long as there is a favourable response.
With obvious disease progression, discontinue TAMOFEN. However, because an occasional
patient will have a local disease flare (see description under Adverse Reactions) or an increase in
bone pain shortly after starting TAMOFEN, it is sometimes difficult during the first few weeks of
treatment to determine whether the patient's disease is progressing, or whether it will stabilize or
respond to continued treatment. There are data to suggest that, if possible, treatment should not
be discontinued before a minimum of three to four weeks.
Drug Interaction: When tamoxifen is used in combination with cytotoxic agents, there is increased
risk of thromboembolic events occurring.
The most frequent adverse reactions to TAMOFEN (tamoxifen) are hot flushes, nausea and
vomiting. These may occur in up to 25% of patients and are rarely severe enough to require
discontinuation of treatment.
Less frequently reported adverse reactions are vaginal bleeding and vaginal discharge. Any
patients reporting these symptoms should be promptly investigated. An increased incidence of
uterine cancer and uterine sarcomas has been reported in association with tamoxifen treatment
Skin rashes, have also been reported. Usually these have not been severe enough to require
dosage reduction or discontinuation of treatment.
Increased bone and tumor pain and also local disease flare have occurred. These are sometimes
associated with good tumor response. Patients with soft tissue disease may have sudden increases
in the size of pre-existing lesions, sometimes associated with marked erythema within and
surrounding the lesions, and/or the development of new lesions. When they occur, the bone pain
or disease flare are seen shortly after starting TAMOFEN and generally subside rapidly.
Ocular changes have been reported in a few breast cancer patients who, as part of a clinical trial,
were treated for periods longer than one year with doses of tamoxifen that were at least four times
the highest recommended daily dose of 40 mg. In each instance, the total amount of drug exceeded
100 grams. These changes were a retinopathy and, in a few patients, corneal changes and
decreased visual acuity. There were multiple light refractile opacities in the paramacular area, and
macular edema. The corneal lesions consist of whorl-like superficial opacities.
A number of cases of visual disturbances, including infrequent reports of corneal changes, and
retinopathy have been described in patients receiving tamoxifen therapy. An increased incidence
of cataracts has been reported in association with the administration of tamoxifen.
Leukopenia has been observed following the administration of tamoxifen, sometimes in association
with anemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can
sometimes be severe.
Elevations of alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) and gamma-
glutamyl transpeptidase (GT) levels have been reported on rare occasions in association with
tamoxifen therapy. The incidence of overt cholestasis appears to be very low (<1%) but it should
be kept in mind while administering tamoxifen over the long term.
There have been infrequent reports of thromboembolic events occurring during tamoxifen citrate
therapy. As an increased incidence of these events is known to occur in patients with malignant
disease, a causal relationship with tamoxifen citrate has not been established.
symptomatic hepatic cysts, peliosis hepatitis, distaste for food, pruritus vulvae, depression,
dizziness, light headedness and headache.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps
have been reported. Ovarian cysts have been observed in a small number of pre-menopausal
patients with advanced breast cancer who have been treated with tamoxifen.
Importantly, increased incidence of uterine malignancies, including endometrial adenocarcinomas
and uterine sarcomas, have been reported in association with tamoxifen therapy (see WARNINGS).
In the prevention section, treatment with tamoxifen has been associated with an increased risk of
stroke (see WARNINGS).
O C H
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Symptoms: Acute overdosage in humans has not been reported. Possible overdosage effects might
include hot flushes, nausea, vomiting and vaginal bleeding.
Treatment: Symptomatic treatment. In the case of childhood accidental ingestion, gastric emptying
DOSAGE AND ADMINISTRATION
The usual dose is 20 to 40 mg per day in a single or two divided doses. Use the lowest effective
In early disease, the recommended duration of therapy is 5 years. The optimal duration of therapy
remains to be determined.
dimethylethylamine citrate (1:1).
Tamoxifen citrate is a fine white, odourless crystalline powder. It is soluble in methanol, sparingly
soluble in ethanol and acetone, and very slightly soluble in water. It is hygroscopic and
Stability and Storage recommendations:
Store at room temperature (between 15 and 30°C) in a well closed container. Protect from light.
TAMOFEN (tamoxifen citrate) 10 mg tablets - white, round, biconvex tablets, marked T/10 on one
side and scored on the other; contains 15.2 mg tamoxifen citrate equivalent to 10 mg of tamoxifen
base. Non-Medicinal ingredients: lactose monohydrate, maize starch, silica colloidal anhydrous,
povidone, talc, magnesium stearate and purified water. Plastic containers of 60 and 250 tablets;
or boxes of 60 tablets in aluminium film strips (unit dose packages).
TAMOFEN (tamoxifen citrate) 20 mg tablets - white round, biconvex tablets, marked T/20 on one
side; contains 30.4 mg tamoxifen citrate equivalent to 20 mg tamoxifen base. Non-Medicinal
ingredients: lactose monohydrate, maize starch, silica colloidal anhydrous, povidone, talc,
magnesium stearate and purified water. Plastic containers of 60 tablets; or boxes of 30 and 60
tablets in aluminium film strips (unit dose packages).
INFORMATION FOR THE PATIENT
Tamoxifen is a medicine that blocks the effects of the hormone estrogen in the body. It is used to
treat breast cancer.
The exact way that tamoxifen works against cancer is not known, but it may be related to the way
it blocks the effects of estrogen on the body.
Tamoxifen is available only with your doctor's prescription.
Before Using this Medication
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good
it will do. This is a decision you and your doctor will make.
Before taking tamoxifen, tell your doctor if any of the following apply to you:
If you have ever had any unusual or allergic reaction to tamoxifen or any one of its
ingredients (See What Does TAMOFEN Contain).
If you have a history of blood clots, including deep vein thrombosis (a blood clot in one of
the deep veins of the body - usually within the leg).
If you have a history of pulmonary embolism (obstruction of a pulmonary artery by foreign
matter such as fat, air, tumor tissue or a blood clot).
If you have a history of stroke.
If you intend to become pregnant. It is best to use some kind of birth control while you are
taking tamoxifen and for about two months after you stop taking it. Please see your doctor
for advice on what contraceptive precautions you should take, as some may be affected by
tamoxifen. Tell your doctor right away if you think you have become pregnant while taking
tamoxifen or within two months of having stopped it.
It is important that you tell your doctor immediately if you have any unusual vaginal bleeding
when you are taking tamoxifen or anytime afterwards. This is because a number of changes
to the lining of the womb (the endometrium) may occur, some of which may be serious and
could include cancer.
If you are breastfeeding or intend to breastfeed.
If you are taking any other prescription or over-the-counter medicine.
If you have any other medical problems, especially cataracts (or other eye problems) or low
blood cell counts.
If you go into the hospital, let medical staff know you are taking tamoxifen.
Who Should Not Take TAMOFEN
If you have ever had any unusual or allergic reaction to tamoxifen or any one of its
ingredients (See What Does TAMOFEN Contain).
If you are pregnant or if you intend to become pregnant.
Proper Use of This Medication
Use this medication as directed by your doctor. Do not use more or less of it and do not use it more
often than your doctor ordered. Taking too much may increase the chance of side effects, while
taking too little may not improve your condition.
Tamoxifen sometimes causes nausea and vomiting. However, it may have to be taken for several
weeks or months to be effective. Even if you begin to feel ill, do not stop using this medicine without
first checking with your doctor. Ask your health care professional for ways to lessen these effects.
Missed dose - If you miss a dose, take the dose as soon as you remember. Do not take two doses
at the same time.
What Does TAMOFEN Contain
The medicinal ingredient of TAMOFEN is the tamoxifen citrate. Each tablet of TAMOFEN also
contains the following non-medicinal ingredients: lactose monohydrate, maize starch, silica colloidal
anhydrous, povidone, talc, magnesium stearate and purified water.
To Store this Medicine:
KEEP OUT OF THE REACH OF CHILDREN.
Store away from heat and direct light.
Do not store in damp places. Heat or moisture may cause the medicine to break down.
Do not keep outdated medicine or medicine no longer needed.
Precautions While Using this Medicine
It is important to use some type of birth control while you are taking tamoxifen. Please see your
doctor for advice on what contraceptive precautions you should take, as some may be affected by
tamoxifen. Tell your doctor right away if you think you have become pregnant while taking this
medicine or within two months of stopping it.
Side Effects of This Medicine
Along with its needed effects, a medicine may cause some unwanted effects. Some side effects will
have signs or symptoms that you can see or feel. Your doctor will watch for others by doing certain
Also, because of the way this medicine acts on the body, there is a chance that it might cause other
unwanted effects that may not occur until months or years after the medicine is used. Tamoxifen has
been reported to increase the chance of cancer of the uterus (womb) as well as fibroids (non-
cancerous tumors) in the uterus in some women taking it. It may also cause a drop in some of your
blood cell counts. In addition, tamoxifen has been reported to cause cataracts and other eye
problems. Discuss these possible effects with your doctor.
Check with your doctor or pharmacist as soon as possible if any of the following undesirable events
Do not be alarmed by this list of possible events. You may not have any of them.
Effects on the endometrium (lining of the womb), which may also be seen as vaginal
Fibroids (causes enlargement of the womb), which may also be seen as discomfort in the
pelvis or as vaginal bleeding
Itching around the vagina
Stomach upsets (including nausea and vomiting)
Fluid retention (possibly seen as swollen ankles)
Bruising more easily (thrombocytopenia)
Certain liver problems such as jaundice (yellow eyes)
Disturbances of vision
Difficulties in seeing properly possibly due to cataracts, changes to the cornea or disease of
Ovarian cysts (fluid sacs on ovaries) in premenopausal women
Increased risk of blood clots
Pain, swelling or redness of the calf or leg which may indicate a blood clot
Chest pain or shortness of breath which may indicate a blood clot
Symptoms of stroke, such as weakness, difficulty walking or talking, or numbness
At the beginning of treatment, a worsening of the symptoms of your breast cancer such as
an increase in pain and/or an increase in the size of the affected tissue may occur. In
addition, if you experience excessive nausea, vomiting and thirst, you should tell your doctor.
This may indicate possible changes in the amount of calcium in your blood and your doctor
may have to do certain blood tests.
Other side effects not listed above may also occur in some patients. If you notice any other effects,
check with your doctor.
If you need further information ask your doctor or pharmacist.
In animal species tamoxifen usually acts as an anti-estrogen compound inhibiting the effects of
exogenous estrogen probably by binding with cytoplasmic estrogen receptors with subsequent
translocation into the nucleus but without producing typical estrogen response. In rodents however
it can also induce atypical or weak estrogenic effects.
In those species in which tamoxifen is an estrogen antagonist, this property is manifest in various
ways. Thus in spayed rats, vaginal cornification in response to the daily subcutaneous injection of
estradiol can be prevented by concomitant oral dosing with tamoxifen and in immature rats the
uterotrophic effect of estrogen can be similarly inhibited.
Also in rats, tamoxifen will terminate early pregnancy by preventing implantation of the blastocysts.
It is known that, in rats, estrogen secreted by the ovaries on day 4 of pregnancy initiates implantation
(on day 5). There is evidence that, at the lowest dose needed to prevent implantation, tamoxifen
acts by counteracting this estrogen.
In normal female rats having regular estrous cycles, ovulation can be delayed by administration of
a single dose of tamoxifen given on or before the day of diestrous. In the rat (and other
spontaneously ovulating species), it appears that the ovulatory discharge of luteinizing hormone (LH)
from the pituitary is "triggered" by the action of estrogen on the hypothalamus and/or pituitary. The
secretion of estrogen from the ovaries reaches a peak before this LH discharge. The inhibitory effect
of tamoxifen on ovulation is attributed to interference with the "feedback" action of estrogen at the
hypothalamic and/or pituitary level.
In the pig-tailed monkey (M. nemestrina), the activity of tamoxifen as an estrogen antagonist is
shown by its effect on the response to estrogen of the perineal region ("sexual skin"). Mature
females of this species menstruate regularly at intervals of about 28 days. An edematous swelling
of the "sexual skin" develops during the follicular phase of the cycle and subsides more rapidly at
about the presumed time of ovulation. The swelling is due to endogenous estrogen and is not seen
in the ovariectomized animals unless estrogen is given. In an ovariectomized pig-tail, large daily
doses of tamoxifen caused no swelling of the "sexual skin". On the other hand, the swelling induced
by daily injection of estradiol was reduced almost to zero by small (oral) doses of tamoxifen given
at the same time.
Although the capacity of tamoxifen (demonstrated in spayed rats and monkeys) to inhibit the
response to estrogen suffices to explain its effects, outlined above, in intact animals of these
species, the possibility that it may also inhibit the endogenous production of estrogen cannot yet be
In very large doses, tamoxifen causes a limited increase in uterine weight and incomplete vaginal
cornification in spayed rats, indicating that it has some degree of estrogenic activity. In one species,
the mouse, it behaves as an estrogen without demonstrable estrogen antagonistic activity at any
Tamoxifen has been shown to inhibit or reverse the growth of some dimethylbenzathracene (DMBA)-
induced carcinomas in rats and to decrease the frequency of tumor development when administered
concurrently with DMBA. The responsiveness of DMBA-induced tumors was correlated with their
In studies using estrogen-dependent human cancer cell cultures tamoxifen inhibited cell production,
macromolecules. The simultaneous addition of estrogen to tumor cultures along with tamoxifen
either prevented or reversed tamoxifen's inhibitory effect. However, incubation of tumor cells with
tamoxifen alone for longer that 3 days produced irreversible inhibition of growth.
Pharmacokinetics and Metabolism
The absorption, distribution and excretion of tamoxifen have been studied with radio-labelled
tamoxifen. After a single dose of 20 mg of tamoxifen maximum blood levels occurred at 4 to 7 hours
after drug administration whereby 20% to 30% of the original radioactivity were found in plasma.
Radioactivity in the uterus was about twice that in the serum. The highest concentration occurred
in the endometrium. The distribution half-life was about 7 to 14 hours after single dose. However
after continued administration it was greatly prolonged (7 days).
The elimination of tamoxifen is biphasic. A considerable enterohepatic circulation has been
demonstrated which probably is the reason for the slow elimination. Tamoxifen is mainly excreted
in the feces with only small amounts appearing in the urine. Tamoxifen is primarily excreted as
conjugates with unchanged drug and hydroxylated metabolites accounting for 30% of the total.
The two major metabolites are 4-hydroxytamoxifen and desmethyltamoxifen. Both possess
A cross-over bioavailability study has also been carried out in which RHÔNE-POULENC's brand
TAMOFEN was compared to NOLVADEX (ICI): thirty-two healthy males volunteers took part in the
study; each subject received a single oral dose of 2 x 10 mg tablets of tamoxifen. A drug-free interval
of 70 days was allowed between the administration of the two brands.
Following drug administration, plasma concentrations of tamoxifen were determined over a 21-day
period by H.P.L.C. The mean comparative pharmacokinetic parameters of the two brands of
tamoxifen tablets are presented in the following table.
Mean pharmacokinetic parameters of tamoxifen (± SEM)
(32 subjects: single dose; 2 x 10 mg tablets)
38.2 ± 1.30
4.4 ± 0.20*
109.3 ± 8.85
2338.9 ± 118.57
99.2 ± 5.36 %
37.6 ± 1.58
5.1 ± 0.30*
112.3 ± 7.44
*significantly different p < 0.05
pharmacokinetic properties of tamoxifen, this difference has no clinical significance.
The power of the study to detect a 20% difference between TAMOFEN and NOLVADEX was greater
than 0.99 for Cmax and greater than 0.93 for AUC .
The steady-state relative bioavailability of TAMOFEN was determined in 16 patients with advanced
breast carcinoma in a randomized, multiple-dosing, cross-over study. Each patient received
tamoxifen 20 mg daily as TAMOFEN or NOLVADEX for a period of 8 weeks at which point the
medications were cross-over for another 8 weeks of treatment. At the end of each medication period,
plasma samples were collected over one dosing interval. Plasma concentrations of tamoxifen (T),
determined by HPLC. The corresponding AUC's were as follows:
Mean AUC values of tamoxifen and metabolites (± SEM) (h.ng.mL
2987 ± 301.5
5345 ± 435.3
890 ± 108.8
2904 ± 265.3
5211 ± 363.8
1165 ± 104.3
859 ± 92.3
No significant difference was observed in the availability of any of tamoxifen or any of its metabolites.
Acute toxicity studies
The following table summarizes the main findings of the acute toxicity studies carried out with
tamoxifen in mice and rats:
animals per group
Dosage and route
Long-term toxicity studies
Sub-acute and chronic toxicity studies have been carried out in mice, rats, dogs and monkeys with
daily oral doses of tamoxifen. The following table summarizes the pertinent findings of these studies.
Dosage and route
Observations & Findings
2, 20, 100 mg/kg
Effects primarily on the reproductive
Oral up to 75 mg/kg
Effects primarily on the reproductive
Biliary stasis also seen at the highest
Oral 0.1 to 50 mg/kg
Testicular and ovarian tumors and
All females and 3 males died within
the first 2 weeks. Toxic symptoms
included bleeding from nose, pilo-
erection and weakness. Slight
leukopenia, thrombo-cytopenia and
anemia in male rats.
At autopsy enlargement of adrenals
and smaller thymus and seminal
35, 70 mg/kg
50% of females and 17% of males
died at both dose levels. Food intake
increased, nose bleeding and
decreased locomotor activity. At
autopsy there was an increase in
adrenal size and decrease in genital
size. Histopathology showed atrophy
of reproductive system and
hyperplasia of adrenal cortex. Slight
anemia and thrombo-cytopenia were
0.6, 6, 60 mg/kg
(followed by 7-week
At high dose: death of 40% of males
and 20% of females; evidence of
preneoplastic and/or neoplastic liver
Other toxic symptoms included;
severe decrease in body weights, loss
of hair, cataracts in 12% of animals at
high dose, atrophic changes of
reproductive organs and increase in
0.007, 0.7, 35 mg/kg
At intermediate and high dose: severe
atrophic changes of reproductive
At high dose: slight anemia,
leukopenia and thrombocytopenia;
nodular hyperplasia of hepatocytes.
5, 15, 45 mg/kg
(70 mg/kg x 2 days
but badly tolerated)
(followed by 5-week
One death at 70 mg/kg. At
histopathology (in one or more
animals): altera-tion of digestive
mucosa, atrophy of splenic corpus-
cules, and thymic cortex, calcification
of myocardial cells, tubular cell necro-
sis, minor alterations of
Four separate mutagenicity studies have been carried out with Tamoxifen. The following table
summarizes the results of these investigations.
Strains or Species
Tamoxifen citrate 0.05,
0.15, 0.50, 1.50, 5.0
showed no increase in
mutant colonies, but
strong toxicity at 5.0
mg/mL and moderate
toxicity at 1.5 mg/mL.
Positive controls were
Tamoxifen citrate 5, 20
and 80 mg/kg.
Negative control group
Positive control group
showed a significant
increase in polychro-
matic erythrocytes at
all dose levels in
comparison to the
negative control group
but signifi-cantly less
than the positive
TA1539, TA100 and
Tamoxifen 0, 1, 10,
100, 1000 /plate
No evidence of
mutagenic activity of
tamoxifen was ob-
served either in the
presence or absence
of liver microsomal
fibroblast (FH 109 line)
Tamoxifen citrate 0.25,
0.5, 1.0, 2.0, 4.0 g/mL
No significant in-
crease in mean
number of sister
Positive at concen-
trations of 1 g/mL and
Tamoxifen is not mutagenic in a range of in vitro and in vivo mutagenicity studies. Tamoxifen was
genotoxic in some in vitro tests and in vivo genotoxicity tests in rodents.
ESTROGEN RECEPTOR ASSAY
Recently, studies in estrogen-dependent tissues have led to the discovery of a cytoplasmic protein
which binds estrogen with high affinity and specificity. Estrogen enters the cytoplasm of all cells
whether or not they are estrogen-dependent. However, in the cytoplasm of estrogen-dependent cells
are found specific protein molecules that are termed receptors. These receptor proteins bind
estrogen biologically with great affinity and specificity.
Following this initial binding step, the estrogen receptor complex undergoes an activation which
allows the complex to enter the nucleus of the cell and bind to chromatin, the genetic information of
the cells. Once bound to the chromatin, the interaction of the estrogen receptor complex with the
genetic information of the cell leads to the elaboration of new species of messenger RNA. These
molecules are then released into the cytoplasm where they can be translated on polysomes into new
Antiestrogens are also able to enter the cytoplasm of the estrogen-dependent cell and bind
biologically to the protein receptor with affinity and specificity, thus activating the complex to also
translocate to the nucleus. However, the normal estrogen transcriptional processes are altered.
Hence, antiestrogens interfere with estrogen-dependent tumor growth by competing with estrogens
for the receptor site and by turning off the normal processes of the genetic information within the
Reports concerning the relationship between clinical responses of patients with breast cancer
receiving endocrine therapy and the presence or absence of estrogen receptors have been
In patients with tumors positive for estrogen receptors, the response rate to endocrine therapy was
approximately 56%; and in patients with tumors negative for estrogen receptors, the response rate
was about 10%. It was concluded that estrogen receptor assays are useful in predicting the results
of endocrine therapy in patients with breast cancer.
Dextran-coated charcoal assay (DCC)
The Dextran-coated charcoal assay (DCC) involves the extraction of the highly labile
estradiol receptor from a cytosol prepared from the tumor tissue. After incubating with tritiated
estradiol, which interacts with the binding sites of receptors, the excess estradiol is separated from
the incubate with dextran-coated charcoal. The amount of nonspecific binding (e.g., albumin) is then
determined and the quantity of estradiol receptors in the tissue is estimated from the difference in
the total binding less nonspecific binding per milligram of protein. Tumors which show binding
capacity similar to benign tumors are designated ER-negative, while those with higher binding
capacity are designated ER-positive.
Sucrose gradient method (SG)
The weighed tumor specimen is immersed in liquid nitrogen and shattered. The residual
tissue powder is homogenized with efficient cooling in four volumes of buffer, using a tissue
disintegrator with two or three homogenization periods, each followed by a cooling period. The
homogenate is centrifuged to precipitate the particulate matter. Two portions of the cytosol fraction
are removed and treated with either buffer alone or buffer containing an agonist. When equilibrium
is reached, tritiated estradiol is added to each mixture. After mixing and standing in the cold, a
portion of each mixture is layered on a 10 to 30% sucrose gradient containing buffer, and
centrifuged. Successive fractions are collected, from which the radioactivity is counted.
Receptor-positive tumor specimens exhibit 8 S complex, whereas others show various amounts of
specific binding in the 4 S region as well. Radioactivity associated with the 8 S form of estrophilin
is estimated from the difference in the sedimentation curves, with and without inhibitor, from fraction
1 to the minimum observed around fractions 18 to 22, depending on the ultra-centrifugation. The 4 S
radioactivation is similarly calculated by difference of the curves between the minimum and the point
where the curve with inhibitor crosses the curve without inhibitor.
Interpretation of results
Laboratory results of the estrogen receptor assay should be interpreted by a qualified expert, as
results may vary due to technique, handling and storage of the specimen, and the patient's
menopausal status or recent drug therapy. Quantitative results vary among laboratories and
methods. As a result of retrospective correlation made by various investigators based upon patient's
response to hormonal manipulation, a result of less than 3 fmoL/mg of cytosol protein is considered
ER-negative, 3 to 10 fmoL/mg cytosol protein is equivocal and over 10 fmoL/mg is considered ER-
De QUIJADA M et al.
Tamoxifen enhances the sensitivity of dispersed prolactin secreting pituitary tumor cells to
dopamine and bromocriptine.
Endocrinology 1980; 106(3): 702-706
HARPER MJK et al.
A new derivative of triphenylethylene. Effects of implantation and mode of action in rats.
J Reprod Fertility, 1967; 13: 101-119
Tamoxifen: A review of its pharmacological properties and therapeutic use in the treatment
of breast cancer.
Drugs, 1978; 16(1): 1-24
JORDAN VC et al.
Tamoxifen as an anti-tumor agent: oestrogen binding as a predictive test for tumor
J Endocrinol, 1976; 68(3): 453-60
NICHOLSON Robert I et al.
Effects of oestradiol-17B and tamoxifen on total and accessible cytoplasmic oestradiol-17B
receptors in DMBA-induced rat mammary tumors.
Eur J Cancer, 1976; 12(9): 711-17
ADAM HK et al.
Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers.
Cancer Treat Rep, 1980; 64(6-7): 761-64
DANIEL CP et al.
Determination of tamoxifen and hydroxylated metabolites in plasma from patients with
advanced breast cancer using gas chromatography-mass-spectrometry.
J Endocr, 1979; 83: 401-408
FABIAN C et al.
Clinical pharmacology of tamoxifen in patients with breast cancer.
Cancer, 1981; 48: 876-82
FROMSON JM et al.
The metabolism of tamoxifen. Part I - In laboratory animals.
Xenobiotica, 1973; 11(3): 693-709
The metabolism of tamoxifen. Part II - In female patients.
Xenobiotica, 1973; 11(3): 711-714
KLEIMOLA T et al.
Bioavailability study of Tamofen 10 mg, tamoxifen tablet, following a single dose (biostudy
of Tamofen 10 mg).
Data on file Rhône-Poulenc Rorer Canada Inc. (1985)
SOININEN K et al.
The steady-state pharmacokinetics of tamoxifen and its metabolites in breast cancer
J Int Med Res 1986; 14: 162-165
WILKINSON P et al.
Clinical pharmacology of tamoxifen and N-desmethyl tamoxifen in patients with advanced
Cancer Chemother Pharmacol, 1980; 5: 109-111
BAUM M et al.
Controlled trial of tamoxifen as adjuvant in management of early breast cancer.
Lancet, 1983 Feb 5 ; 1(8319): 257-260
CAMPBELL FC et al.
Quantitative oestradiol receptor values in primary breast cancer and response of metastases
to endocrine therapy.
Lancet, 1981 Dec 12, ; 2(8259): 1317-1319
COLE MP et al.
Tamoxifen, clinical experience in 129 patients with advanced breast cancer.
Hormones and Breast Cancer, May 1975; 35: 245-246
Cancer principles and Practice of Oncology. Philadelphia
Lippincott Co. IXBNO-397-500440-3, 1982; 945-949
LEGHA SS et al.
Hormonal therapy of breast cancer. New approaches and concepts.
Ann Intern Med, 1978; 88: 69-77
MAUNI A et al.
Anti-oestrogen-induced remissions in stage IV breast cancer.
Cancer Treat Rep, 1976; 60: 1445-1450
McGUIRE William L
Estrogen receptors in human breast cancer: an overview.
Raven Press - New York, North Holland Publc. Co. 1975
MOURIDSEN Henning et al.
Tamoxifen in advanced breast cancer.
Cancer Treat Revs, 1978; 5: 131-141
TORMEY, Douglas C. et al.
Evaluation of tamoxifen dose in advanced breast cancer.
Cancer Treat Rep, 1976; 60: 1451-1459