TAMOFEN 20 TABLET

Canada - English - Health Canada

Buy It Now

Active ingredient:
TAMOXIFEN (TAMOXIFEN CITRATE)
Available from:
SANOFI-AVENTIS CANADA INC
ATC code:
L02BA01
INN (International Name):
TAMOXIFEN
Dosage:
20MG
Pharmaceutical form:
TABLET
Composition:
TAMOXIFEN (TAMOXIFEN CITRATE) 20MG
Administration route:
ORAL
Units in package:
30/60
Prescription type:
Prescription
Therapeutic area:
ANTINEOPLASTIC AGENTS
Product summary:
Active ingredient group (AIG) number: 0131293002; AHFS: 10:00.00
Authorization status:
APPROVED
Authorization number:
01926632
Authorization date:
2006-06-15

Documents in other languages

PRODUCT MONOGRAPH

TAMOFEN

(Tamoxifen Citrate)

10 and 20 mg Tablets

Antineoplastic

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

TAMOFEN

tamoxifen citrate tablets 10 mg and 20 mg

THERAPEUTIC CLASSIFICATION

Antineoplastic (non-steroidal antiestrogen)

AMOXIFEN THERAPY WAS ASSOCIATED WITH SERIOUS AND LIFE

THREATENING EVENTS INCLUDING UTERINE

MALIGNANCIES

STROKE

PULMONARY EMBOLISM

AND DEEP VEIN THROMBOSIS IN THE

ATIONAL

URGICAL

DJUVANT

REAST AND

OWEL

ROJECT

(NSABP)

BREAST CANCER PREVENTION TRIAL

HE USE OF

TAMOXIFEN FOR BREAST CANCER PREVENTION IS NOT AN APPROVED INDICATION IN

ANADA

FOLLOWING RISKS ASSOCIATED WITH TAMOXIFEN THERAPY HAVE BEEN ESTIMATED FROM THE

NSABP

BREAST CANCER PREVENTION TRIAL

HE RELATIVE RISK OF TAMOXIFEN COMPARED TO PLACEBO WAS

FOR ENDOMETRIAL CANCER

FOR UTERINE SARCOMAS

FOR STROKE

FOR PULMONARY

EMBOLISM

FOR DEEP VEIN THROMBOSIS

HESE EVENTS WERE FATAL IN SOME PATIENTS

EALTH

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

(see

WARNINGS

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

tumor growth.

It is recognized that tamoxifen also displays estrogenic-like effects on several body systems

including the endometrium, bone and blood lipids.

INDICATIONS

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.

CONTRAINDICATIONS

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.

WARNINGS

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

cataracts.

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

section.

PRECAUTIONS

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

tamoxifen

therapy,

complete

blood

counts,

including

platelet

counts,

should

obtained

periodically.

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.

ADVERSE REACTIONS

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

(see WARNINGS).

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.

Other

adverse

reactions

noted

infrequently

hypercalcemia,

peripheral

edema,

benign

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

is suggested.

DOSAGE AND ADMINISTRATION

The usual dose is 20 to 40 mg per day in a single or two divided doses. Use the lowest effective

dose.

In early disease, the recommended duration of therapy is 5 years. The optimal duration of therapy

remains to be determined.

PHARMACEUTICAL INFORMATION

Tamoxifen

citrate

trans-isomer

(Z)-2-[p-(1,2-Diphenyl-1

butenyl)

phenoxy]-N,

dimethylethylamine citrate (1:1).

Molecular formula:

NO. C

Molecular weight:

563.65

Description:

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

photosensitive.

Melting point

About 142°C.

Stability and Storage recommendations:

Store at room temperature (between 15 and 30°C) in a well closed container. Protect from light.

DOSAGE FORMS

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

Description

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

tests.

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

occur:

Do not be alarmed by this list of possible events. You may not have any of them.

Hot flushes

Menstrual disturbances

Effects on the endometrium (lining of the womb), which may also be seen as vaginal

bleeding

Fibroids (causes enlargement of the womb), which may also be seen as discomfort in the

pelvis or as vaginal bleeding

Itching around the vagina

Vaginal discharge

Stomach upsets (including nausea and vomiting)

Light-headedness

Fluid retention (possibly seen as swollen ankles)

Bruising more easily (thrombocytopenia)

Skin rash

Hair loss

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

the retina

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.

PHARMACOLOGY

Pharmacodynamics

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

excluded.

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

dose.

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

estrogen-binding capacity.

In studies using estrogen-dependent human cancer cell cultures tamoxifen inhibited cell production,

determined

measuring

rate

incorporation

radiolabelled

thymidine

into

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

antiestrogenic activity.

Bioavailability

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)

Brand

Cmax (ng/mL)

Tmax

(h.ng.mL-1)

Relative

Bioavailability

Tamofen

38.2 ± 1.30

4.4 ± 0.20*

109.3 ± 8.85

2338.9 ± 118.57

99.2 ± 5.36 %

Nolvadex

37.6 ± 1.58

5.1 ± 0.30*

112.3 ± 7.44

2474.1 ±136.89

*significantly different p < 0.05

significant

difference

between

brands

detected

Tmax

values.

Considering

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),

N-desmethyltamoxifen

(DMT),

N,N-didesmethyltamoxifen

(DDMT)

metabolite

were

determined by HPLC. The corresponding AUC's were as follows:

Mean AUC values of tamoxifen and metabolites (± SEM) (h.ng.mL

Brand

Tamoxifen

DDMT

Tamofen

2987 ± 301.5

5345 ± 435.3

1148 ±119.3

890 ± 108.8

Nolvadex

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.

TOXICOLOGY

Acute toxicity studies

The following table summarizes the main findings of the acute toxicity studies carried out with

tamoxifen in mice and rats:

Species

Number of

animals per group

Dosage and route

of administration

LD50

(mg/kg)

Symptomatology

Mice

p.o.

3900

Mice

i.p.

Mice

5/sex/dose

i.v.

Convulsions

Rats

10/female/dose

p.o.

750*

Convulsions

*14 days

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.

Species

Dosage and route

Duration

Observations & Findings

Rats

Oral

2, 20, 100 mg/kg

3 months

Effects primarily on the reproductive

system.

Dogs

Oral up to 75 mg/kg

3 months

Effects primarily on the reproductive

system.

Biliary stasis also seen at the highest

dose

Mice

Oral 0.1 to 50 mg/kg

14-15 months

Testicular and ovarian tumors and

bone changes

Rats

12/sex/dose

Oral

100 mg/kg

29 days

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

vesicles.

Rats

12/sex/dose

Oral

35, 70 mg/kg

3 months

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

also noted.

Rats

25/sex/dose

Oral

0.6, 6, 60 mg/kg

6 months

(followed by 7-week

recovery period)

At high dose: death of 40% of males

and 20% of females; evidence of

preneoplastic and/or neoplastic liver

lesions.

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

adrenal weights.

Rats

10/sex/dose

Oral

0.007, 0.7, 35 mg/kg

6 months

At intermediate and high dose: severe

atrophic changes of reproductive

organs.

At high dose: slight anemia,

leukopenia and thrombocytopenia;

nodular hyperplasia of hepatocytes.

Monkeys

(Callitrix jacchus)

2/sex/dose

Oral

5, 15, 45 mg/kg

(70 mg/kg x 2 days

but badly tolerated)

6 months

(followed by 5-week

recovery period)

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

spermatogenesis.

Mutagenicity studies

Four separate mutagenicity studies have been carried out with Tamoxifen. The following table

summarizes the results of these investigations.

Test

Strains or Species

Drug/Dosage

Results

"Mohn" test

E. coli

Tamoxifen citrate 0.05,

0.15, 0.50, 1.50, 5.0

mg/mL

Tamoxifen citrate

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

Micronucleus test

Mice

Tamoxifen citrate 5, 20

and 80 mg/kg.

Negative control group

(sodium citrate).

Positive control group

(cyclophosphamide)

Tamoxifen citrate

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

control group.

"Ames" test

Salmonella

Typhimurium strains

TA1538, TA1537,

TA1539, TA100 and

TA98

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

supplement.

Sister chromatid

exchange test

Embryonal lung

fibroblast (FH 109 line)

Human lymphocytes

Tamoxifen citrate 0.25,

0.5, 1.0, 2.0, 4.0 g/mL

Same

No significant in-

crease in mean

number of sister

chromatid exchanges/

46 chromosomes.

Positive at concen-

trations of 1 g/mL and

above.

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

proteins.

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

nucleus.

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

compiled.

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.

Methods

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-

positive.

REFERENCES

Pharmacology

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

HEEL RC

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

response.

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

Pharmacokinetics

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

FROMSON, JM

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

patients.

J Int Med Res 1986; 14: 162-165

WILKINSON P et al.

Clinical pharmacology of tamoxifen and N-desmethyl tamoxifen in patients with advanced

breast cancer.

Cancer Chemother Pharmacol, 1980; 5: 109-111

Clinical

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

DeVITA VT

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

Similar products

Search alerts related to this product

Share this information