TAMOXIFEN CITRATE- tamoxifen citrate tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TAMOXIFEN CITRATE (UNII: 7FRV7310N6) (TAMOXIFEN - UNII:094ZI81Y45)
Available from:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tamoxifen citrate tablets, USP are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen therapy. Tamoxifen citrate tablets, USP are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets, USP are indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to b
Product summary:
20 mg: Containing 30.4 mg tamoxifen citrate, an amount equivalent to 20 mg of tamoxifen. White, round, unscored, biconvex tablet. Debossed with 2233 on one side and WPI on the other side. NDC 68071-5005-3 BOTTLES OF 30 Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container. For more information about tamoxifen citrate, call 1-800-272-5525. Arimidex® is a trademark of AstraZeneca.
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-5005-3

NuCare Pharmaceuticals,Inc.

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MEDICATION GUIDE

Tamoxifen Citrate Tablets, USP

(ta-MOX-I-fen)

Written for women who use tamoxifen to lower their high chance of getting breast cancer or who have ductal

carcinoma in situ (DCIS)

This Medication Guide discusses only the use of tamoxifen to lower the chance of getting breast cancer in

high-risk women and in women treated for DCIS.

People taking tamoxifen to treat breast cancer have different benefits and different decisions to make than

high-risk women or women with ductal carcinoma in situ (DCIS) taking tamoxifen to reduce the chance of

getting breast cancer. If you already have breast cancer, talk with your doctor about how the benefits of

treating breast cancer with tamoxifen compare to the risks that are described in this document.

Why should I read this Medication Guide?

This guide has information to help you decide whether to use tamoxifen to lower your chance of getting

breast cancer.

You and your doctor should talk about whether the possible benefit of tamoxifen in lowering your high

chance of getting breast cancer is greater than its possible risks. Your doctor has a special computer program

or hand-held calculator to tell if you are in the high-risk group. If you have DCIS and have been treated with

surgery and radiation therapy, your doctor may prescribe tamoxifen to decrease your chance of getting

invasive (spreading) breast cancer.

Read this guide carefully before you start tamoxifen. It is important to read the information you get each time

you get more medicine. There may be something new. This guide does not tell you everything about

tamoxifen and does not take the place of talking with your doctor.

Only you and your doctor can determine if tamoxifen is right for you.

What is the most important information I should know about using tamoxifen to reduce the chance of getting

breast cancer?

Tamoxifen is a prescription medicine that is like estrogen (female hormone) in some ways and different in

other ways. In the breast, tamoxifen can block estrogen’s effects. Because it does this, tamoxifen may block

the growth of breast cancers that need estrogen to grow (cancers that are estrogen- or progesterone-receptor

positive).

Tamoxifen can lower the chance of getting breast cancer in women with a higher than normal chance of

getting breast cancer in the next five years (high-risk women) and women with DCIS.

Because high-risk women don’t have cancer yet, it is important to think carefully about whether the possible

benefit of tamoxifen in lowering the chance of getting breast cancer is greater than its possible risks.

This Medication Guide reviews the risks and benefits of using tamoxifen to reduce the chance of getting

breast cancer in high-risk women and women with DCIS. This guide does not discuss the special benefits and

decisions for people who already have breast cancer.

Why do women and men use tamoxifen?

Tamoxifen has more than one use. Tamoxifen is used:

to lower the chance of getting breast cancer in women with a higher than normal chance of getting

breast cancer in the next 5 years (high-risk women).

to lower the chance of getting invasive (spreading) breast cancer in women who had surgery and

radiation for ductal carcinoma in situ (DCIS). DCIS means the cancer is only inside the milk ducts.

to treat breast cancer in women after they have finished early treatment. Early treatment can include

surgery, radiation, and chemotherapy. Tamoxifen may keep the cancer from spreading to other parts

of the body. It may also reduce the woman’s chance of getting a new breast cancer.

in women and men, to treat breast cancer that has spread to other parts of the body (metastatic breast

cancer).

This guide talks only about using tamoxifen to lower the chance of getting breast cancer (#1 and #2 above).

What are the benefits of tamoxifen to lower the chance of getting breast cancer in high-risk women and in

women treated for DCIS?

A large U.S. study looked at high-risk women and compared the ones who took tamoxifen for 5 years with

others who took a pill without tamoxifen (placebo). High-risk women were defined as women who have a

1.7% or greater chance of getting breast cancer in the next 5 years, based on a special computer program. In

this study:

Out of every 1000 high-risk women who took a placebo, each year about 7 got breast cancer.

Out of every 1000 high-risk women who took tamoxifen, each year about 4 got breast cancer.

The study showed that on average, high-risk women who took tamoxifen lowered their chances of getting

breast cancer by 44%, from 7 in 1000 to 4 in 1000.

Another U.S. study looked at women with DCIS and compared those who took tamoxifen for 5 years with

others who took a placebo. In this study:

Out of every 1000 women with DCIS who took placebo, each year about 17 got breast cancer.

Out of every 1000 women with DCIS who took tamoxifen, each year about 10 got breast cancer.

The study showed that on average, women with DCIS who took tamoxifen lowered their chances of getting

invasive (spreading) breast cancer by 43%, from 17 in 1000 to 10 in 1000.

These studies do not mean that taking tamoxifen will lower your personal chance of getting breast cancer.

We do not know what the benefits will be for any one woman who takes tamoxifen citrate to reduce her

chance of getting breast cancer.

What are the risks of tamoxifen?

In the studies described under “ What are the benefits of tamoxifen?”, the high-risk women who took

tamoxifen citrate got certain side effects at a higher rate than those who took a placebo. Some of these side

effects can cause death.

In one study, in women who still had their uterus:

Out of every 1000 women who took a placebo, each year 1 got endometrial cancer (cancer of the

lining of the uterus) and none got uterine sarcoma (cancer of the body of the uterus).

Out of every 1000 women who took tamoxifen, each year 2 got endometrial cancer and fewer than 1

got uterine sarcoma.

These results show that, on average, in high-risk women who still had their uterus, tamoxifen citrate doubled

the chance of getting endometrial cancer from 1 in 1000 to 2 in 1000, and it increased the chance of getting

uterine sarcoma. This does not mean that taking tamoxifen will double your personal chance of getting

endometrial cancer or increase your chance of getting uterine sarcoma. We do not know what this risk will be

for any one woman. The risk is different for women who no longer have their uterus.

For all women in this study, taking tamoxifen increased the risk of having a blood clot in their lungs or veins,

or of having a stroke. In some cases, women died from these effects.

Tamoxifen increased the risk of getting cataracts (clouding of the lens of the eye) or needing cataract surgery.

(See “ What are the possible side effects of tamoxifen?” for more details about side effects.)

What don’t we know about taking tamoxifen citrate to reduce the chance of getting breast cancer?

We don’t know:

if tamoxifen lowers the chance of getting breast cancer in women who have abnormal breast cancer

genes (BRCA1 and BRCA2)

if taking tamoxifen for 5 years reduces the number of breast cancers a woman will get in her lifetime

or if it only delays some breast cancers

if tamoxifen helps a woman live longer

the effects of taking tamoxifen with hormone replacement therapy (HRT), birth control pills, or

androgens (male hormones)

the benefits of taking tamoxifen if you are less than 35 years old

Studies are being done to learn more about the long-term benefits and risks of using tamoxifen to reduce the

chance of getting breast cancer.

What are the possible side effects of tamoxifen?

The most common side effect of tamoxifen is hot flashes. This is not a sign of a serious problem.

The next most common side effect is vaginal discharge. If the discharge is bloody, it could be a sign of a

serious problem. [See “ Changes in the lining (endometrium) or body of your uterus” below.]

Less common but serious side effects of tamoxifen are listed below. These can occur at any time. Call your

doctor right away if you have any signs of side effects listed below:

Changes in the lining (endometrium) or body of your uterus. These changes may mean serious

problems are starting, including cancer of the uterus. The signs of changes in the uterus are:

- Vaginal bleeding or bloody discharge that could be a rusty or brown color. You should call your doctor

even if only a small amount of bleeding occurs.

- Change in your monthly bleeding, such as in the amount or timing of bleeding or increased clotting.

- Pain or pressure in your pelvis (below your belly button).

Blood clots in your veins or lungs. These can cause serious problems, including death. You may get

clots up to 2 to 3 months after you stop taking tamoxifen citrate. The signs of blood clots are:

- sudden chest pain, shortness of breath, coughing up blood

- pain, tenderness, or swelling in one or both of your legs

Stroke. Stroke can cause serious medical problems, including death. The signs of stroke are:

- sudden weakness, tingling, or numbness in your face, arm or leg, especially on one side of your body

- sudden confusion, trouble speaking or understanding

- sudden trouble seeing in one or both eyes

- sudden trouble walking, dizziness, loss of balance or coordination

- sudden severe headache with no known cause

Cataracts or increased chance of needing cataract surgery. The sign of these problems is slow blurring

of your vision.

Liver problems, including jaundice. The signs of liver problems include lack of appetite and

yellowing of your skin or whites of your eyes.

These are not all the possible side effects of tamoxifen. For a complete list, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

Who should not take tamoxifen?

Do not take tamoxifen for any reason if you

Are pregnant or plan to become pregnant while taking tamoxifen or during the 2 months after you

stop taking tamoxifen. Tamoxifen may harm your unborn baby. It takes about 2 months to clear

tamoxifen from your body. To be sure you are not pregnant, you can start taking tamoxifen while you

are having your menstrual period. Or, you can take a pregnancy test to be sure you are not pregnant

before you begin.

Are breast feeding. We do not know if tamoxifen can pass through your milk and harm your baby.

Have had an allergic reaction to tamoxifen or to any of its inactive ingredients.

If you get pregnant while taking tamoxifen, stop taking it right away and contact your doctor. Tamoxifen

may harm your unborn baby.

Do not take tamoxifen to lower your chance of getting breast cancer if:

You ever had a blood clot that needed medical treatment.

You are taking medicines to thin your blood, like warfarin, (also called Coumadin®*).

Your ability to move around is limited for most of your waking hours.

You are at risk for blood clots. Your doctor can tell you if you are at high risk for blood clots.

You do not have a higher than normal chance of getting breast cancer. Your doctor can tell you if you

are a high-risk woman.

How should I take tamoxifen?

Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take tamoxifen with

or without food. Take your medicine every day. It may be easier to remember if you take it at the

same time each day.

If you forget a dose, take it when you remember, then take the next dose as usual. If it is almost time

for your next dose or you remember at your next dose, do not take extra tablets to make up the missed

dose.

Take tamoxifen for 5 years, unless your doctor tells you otherwise.

What should I avoid while taking tamoxifen?

Do not become pregnant while taking tamoxifen or for 2 months after you stop. Tamoxifen can stop

hormonal birth control methods from working. Hormonal methods include birth control pills, patches,

injections, rings and implants. Therefore, while taking tamoxifen, use birth control methods that don’t

use hormones, such as condoms, diaphragms with spermicide, or plain IUD’s. If you get pregnant,

stop taking tamoxifen right away and call your doctor.

Do not breastfeed. We do not know if tamoxifen can pass through your milk and if it can harm the

baby.

What should I do while taking tamoxifen?

Have regular gynecology check-ups (“female exams”), breast exams and mammograms. Your doctor

will tell you how often. These will check for signs of breast cancer and cancer of the endometrium

(lining of the uterus). Because tamoxifen does not prevent all breast cancers, and you may get other

types of cancers, you need these exams to find any cancers as early as possible.

Because tamoxifen can cause serious side effects, pay close attention to your body. Signs you should

look for are listed in “ What are the possible side effects of tamoxifen?”

Tell all of the doctors that you see that you are taking tamoxifen.

Tell your doctor right away if you have any new breast lumps.

General information about the safe and effective use of tamoxifen.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Your doctor

has prescribed tamoxifen only for you. Do not give it to other people, even if they have a similar condition,

because it may harm them. Do not use it for a condition for which it was not prescribed.

This Medication Guide is a summary of information about tamoxifen for women who use tamoxifen to lower

their high chance of getting breast cancer or who have DCIS. If you want more information about tamoxifen,

ask your doctor or pharmacist. They can give you information about tamoxifen that is written for health

professionals. For more information about tamoxifen or breast cancer, call 1-800-272-5525.

Ingredients: tamoxifen citrate, croscarmellose sodium, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, and pregelatinized starch.

*Coumadin® is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: April 2015

Revised: 7/2019

Document Id: 8ed73b06-cd8c-534b-e053-2995a90ab730

34391-3

Set id: 8ed73b24-caeb-79ce-e053-2a95a90a2569

Version: 1

Effective Time: 20190729

NuCare Pharmaceuticals,Inc.

TAMOXIFEN CITRATE- tamoxifen citrate tablet

NuCare Pharmaceuticals,Inc.

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Tamoxifen Citrate Tabs_New NDC Codes 2472 2473

Tamoxifen Citrate Tablets, USP

Revised: April 2015

196201- 2

Rx Only

WARNING

For Women With Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast

Cancer

Serious and life-threatening events associated with tamoxifen 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 (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer

Incidence in High Risk Women). Uterine malignancies consist of both endometrial

adenocarcinoma (incidence rate per 1000 women-years of 2.20 for tamoxifen vs. 0.71 for

placebo) and uterine sarcoma (incidence rate per 1000 women-years of 0.17 for tamoxifen

vs. 0.4 for placebo)*. For stroke, the incidence rate per 1000 women-years was 1.43 for

tamoxifen vs. 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1000

women-years was 0.75 for tamoxifen versus 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 tamoxifen to reduce their risk of developing breast cancer.

The benefits of tamoxifen citrate outweigh its risks in women already diagnosed with breast

cancer.

*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP

P-1 study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine

Sarcoma.

**See Table 3 under CLINICAL PHARMACOLOGY, Clinical Studies.

DESCRIPTION

Tamoxifen citrate tablets, USP, a nonsteroidal antiestrogen, are for oral administration. Chemically,

tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-

diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1).

The structural formula is as follows:

NO.C

Molecular Weight: 563.62

The pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it

is 0.2 mg/mL.

10 mg Tablets: Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of

tamoxifen.

20 mg Tablets: Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of

tamoxifen.

Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate,

magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

CLINICAL PHARMACOLOGY

Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal

test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for

binding sites in target tissues such as breast. 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 the

estrogen receptors.

In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for

estrogen receptor protein.

Absorption and Distribution:

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL

(range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma

concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The

average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL).

Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average

steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for tamoxifen and 336 ng/mL

(range 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations

of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3

months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively.

After initiation of therapy, steady-state concentrations for tamoxifen are achieved in about 4 weeks and

steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a

half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg

tamoxifen citrate tablets given twice a day vs. a 20 mg tamoxifen tablet given once daily, the 20 mg

tamoxifen citrate tablet was bioequivalent to the 10 mg tamoxifen citrate tablets.

Metabolis m:

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major

metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be

similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of

tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome

P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion:

Studies in women receiving 20 mg of

C tamoxifen have shown that approximately 65% of the

administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the

primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and

unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Special Populations:

The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined.

The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not

been determined.

Pediatric Patients

The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population

pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients

aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of

tamoxifen in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic

trials in which 59 postmenopausal women with breast cancer completed the studies were included in the

analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model

provided the best fit to the data.

In pediatric patients, an average steady-state peak plasma concentration (C

) and AUC were of 187

ng/mL and 4110 ng hr/mL, respectively, and C

occurred approximately 8 hours after dosing.

Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold

higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6

year olds), CL/F was 2.6-fold higher; in the oldest cohort (7 to 10.9 year olds) CL/F was approximately

1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult

patients. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright

Syndrome and precocious puberty have not been studied beyond one year of treatment. The

long-term effects of tamoxifen therapy in girls have not been established. In adults treated with

tamoxifen an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been

noted (see BOXED WARNING).

Drug-Drug Interactions:

In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited

formation of N-desmethyl tamoxifen with apparent K

of 20, 1, 45 and 30 µM, respectively. The

clinical significance of these in vitro studies is unknown.

Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were

coadministered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and C

by 86%

and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma

concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not

tamoxifen.

In the anastrozole adjuvant trial, coadministration of anastrozole and tamoxifen citrate in breast cancer

patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole

alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-

desmethyltamoxifen (see PRECAUTIONS-Drug Interactions). Tamoxifen citrate should not be

coadministered with anastrozole.

Clinical Studies

ss, max

ss, max

Metastatic Breast Cancer:

Premenopausal Women (Tamoxifen vs. Ablation): Three prospective, randomized studies (Ingle,

Pritchard, Buchanan) compared tamoxifen to ovarian ablation (oophorectomy or ovarian irradiation) in

premenopausal women with advanced breast cancer. Although the objective response rate, time to

treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a

demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard

ratio for death (tamoxifen/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73

to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving

tamoxifen, but the data from the randomized studies do not suggest an adverse effect of this increase. A

limited number of premenopausal patients with disease progression during tamoxifen therapy responded

to subsequent ovarian ablation.

Male Breast Cancer: Published results from 122 patients (119 evaluable) and case reports in 16 patients

(13 evaluable) treated with tamoxifen citrate have shown that tamoxifen is effective for the palliative

treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to tamoxifen which

constitutes a 50% objective response rate.

Adjuvant Breast Cancer:

Overview: The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted worldwide

overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In

1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant

tamoxifen using doses of 20 to 40 mg/day for 1 to 5+ years. Twenty-five percent of patients received 1

year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight

percent of tumors were estrogen receptor (ER) positive (greater than 10 fmol/mg), 21% were ER poor

(less than 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown

breast cancer, 58% were entered into trials comparing tamoxifen to no adjuvant therapy and 42% were

entered into trials comparing tamoxifen in combination with chemotherapy vs. the same chemotherapy

alone. Among these patients, 54% had node positive disease and 46% had node negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5

years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank

2p less than 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for

control (logrank 2p less than 0.00001). Among women with ER positive or unknown breast cancer and

negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for

tamoxifen vs. 73.3% for control (logrank 2p less than 0.00001). The recurrence-free rate at 10 years

was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p less than 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER

positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of tamoxifen, the

proportional reductions in mortality were 12%, 17%, and 26%, respectively (trend significant at 2p less

than 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend

significant at 2p less than 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in

recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral

breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of

about 5 years of tamoxifen on recurrence and mortality were similar regardless of age and concurrent

chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

Anastrozole Adjuvant ATAC Trial - Study of Anastrozole compared to Tamoxifen for Adjuvant Treatment

of Early Breast Cancer: An anastrozole adjuvant trial was conducted in 9366 postmenopausal women

with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole

1 mg daily, tamoxifen citrate 20 mg daily, or a combination of these two treatments for 5 years or until

recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and

tamoxifen citrate did not demonstrate any efficacy benefit when compared with tamoxifen citrate therapy

alone in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was

discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY, Special Populations and

Drug-Drug Interactions, PRECAUTIONS, Laboratory Tests, PRECAUTIONS, Drug

Interactions and ADVERSE REACTIONS for safety information from this trial. Please refer to the

full prescribing information for ARIMIDEX

(anastrozole) 1 mg tablets for additional information on

this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5

years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population

was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the

anastrozole arm compared to the tamoxifen citrate arm.

Node Positive-Individual Studies: Two studies (Hubay and NSABP B-09) demonstrated an improved

disease-free survival following radical or modified radical mastectomy in postmenopausal women or

women 50 years of age or older with surgically curable breast cancer with positive axillary nodes

when tamoxifen was added to adjuvant cytotoxic chemotherapy. In the Hubay study, tamoxifen citrate

was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09

study, tamoxifen was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to

benefit. In the NSABP B-09 study in women age 50 to 59 years, only women with both estrogen and

progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically

significant trend toward adverse effect in women with both estrogen and progesterone receptor levels

less than 10 fmol. In women age 60 to 70 years, there was a trend toward a beneficial effect of

tamoxifen citrate without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using tamoxifen adjuvantly as a single agent

demonstrated an improved disease-free survival following total mastectomy and axillary dissection for

postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The

NATO study also demonstrated an overall survival benefit.

Node Negative-Individual Studies: NSABP B-14, a prospective, double-blind, randomized study,

compared tamoxifen to placebo in women with axillary node-negative, estrogen-receptor positive

(greater than or equal to 10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total

mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation).

After five years of treatment, there was a significant improvement in disease-free survival in women

receiving tamoxifen. This benefit was apparent both in women under age 50 and in women at or beyond

age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for tamoxifen

compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal

women with axillary node-negative breast cancer. In this study, the benefits of tamoxifen appeared to be

independent of estrogen receptor status.

Duration of Therapy: In the EBCTCG 1995 overview, the reduction in recurrence and mortality was

greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a

shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to tamoxifen 20 mg/day for 5 years vs.

placebo and were disease-free at the end of this 5-year period were offered rerandomization to an

additional 5 years of tamoxifen or placebo. With 4 years of follow-up after this rerandomization, 92%

of the women that received 5 years of tamoxifen were alive and disease-free, compared to 86% of the

women scheduled to receive 10 years of tamoxifen (p=0.003). Overall survivals were 96% and 94%,

respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years

does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in

the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95%

CI: 0.87 to 1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant

tamoxifen 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the

patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year

treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the

2-year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in

a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this

difference was not statistically significant.

Contralateral Breast Cancer: The incidence of contralateral breast cancer is reduced in breast cancer

patients (premenopausal and postmenopausal) receiving tamoxifen compared to placebo. Data on

contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview

analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with

tamoxifen of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the

incidence rate of contralateral breast cancer among women receiving tamoxifen were 13% (NS), 26%

(2p = 0.004) and 47% (2p less than 0.00001), with a significant trend favoring longer tamoxifen duration

(2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were

independent of age and ER status of the primary tumor. Treatment with about 5 years of tamoxifen citrate

reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1000 patients in the control

group compared with 3.9 per 1000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant tamoxifen 40 mg/day for 2 to 5

years, the incidence of second primary breast tumors was reduced 40% (p less than 0.008) on tamoxifen

compared to control. In the NSABP B-14 trial in which patients were randomized to tamoxifen 20

mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly

reduced (p less than 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per

1000 patients in the placebo group compared with 5.0 per 1000 patients in the tamoxifen group, at 10

years after first randomization.

Ductal Carcinoma in Situ:

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS).

This trial compared the addition of tamoxifen or placebo to treatment with lumpectomy and radiation

therapy for women with DCIS. The primary objective was to determine whether 5 years of tamoxifen

therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or

contralateral (the opposite) breast.

In this trial 1804 women were randomized to receive either tamoxifen or placebo for 5 years: 902

women were randomized to tamoxifen 10 mg tablets twice a day and 902 women were randomized to

placebo. As of December 31, 1998, follow-up data were available for 1798 women and the median

duration of follow-up was 74 months.

The tamoxifen and placebo groups were well balanced for baseline demographic and prognostic

factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not

palpable, and were detected by mammography alone. Over 60% of the study population was

postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive

after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women

assigned to tamoxifen (44 cases-tamoxifen, 74 cases-placebo; p=0.004; relative risk (RR)=0.57, 95%

CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage

distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data

base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of

events and rate per 1000 women per year for the placebo and tamoxifen groups; and the relative risk

(RR) and its associated 95% confidence interval (CI) between tamoxifen and placebo. Relative risks less

than 1.0 indicate a benefit of tamoxifen citrate therapy. The limits of the confidence intervals can be

used to assess the statistical significance of the benefits of tamoxifen therapy. If the upper limit of the

CI is less than 1.0, then a statistically significant benefit exists.

Table 1: Major Outcomes of the NSABP B-24 Trial

Type of Event

Lumpectomy,

radiotherapy,

and placebo

Lumpectomy,

radiotherapy,

and tamoxifen

RR

95% CI

Limits

No. of

events

Rate per

1000 women

per year

No. of

events

Rate per

1000

women per

year

Invasive Breast Cancer

(Primary Endpoint)

74

16.73

44

9.60

0.57

0.39 to

0.84

Ipsilateral

10.61

5.90

0.56

0.33 to 0.91

Contralateral

5.64

3.71

0.66

0.33 to 1.27

Side undertermined

Secondary Endpoints

DCIS

12.66

8.95

0.71

0.46 to 1.08

Ipsilateral

10.40

8.29

0.88

0.51 to 1.25

Contralateral

2.26

0.65

0.29

0.05 to 1.13

All Breast Cancer Events

29.16

18.34

0.63

0.47 to 0.83

All ipsilateral events

21.70

14.19

0.65

0.47 to 0.91

All contralateral events

8.36

4.37

0.52

0.29 to 0.92

Deaths

Uterine Malignancies

Endometrial Adenocarcinoma

0.57

1.15

Uterine Sarcoma

0.14

Second primary malignancies

(other than endometrial and breast)

Stroke

Thromboembolic events (DVT,

Updated follow-up data (median 8.1 years)

Survival was similar in the placebo and tamoxifen groups. At 5 years from study entry, survival was

97% for both groups.

Reduction in Breast Cancer Incidence in High Risk Women:

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-

controlled trial with a primary objective to determine whether 5 years of tamoxifen citrate therapy (20

mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (see

INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of

ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be

associated with the use of tamoxifen, including: endometrial cancer, pulmonary embolus, deep-vein

thrombosis, stroke, and cataract formation and surgery (see WARNINGS).

The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60

years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used:

years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used:

age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or

absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year

predicted risk of breast cancer of greater than or equal to 1.67% was required for entry into the trial.

In this trial, 13,388 women of at least 35 years of age were randomized to receive either tamoxifen or

placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-

up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782)

and 24% of women randomized to tamoxifen citrate (1,596) completed 5 years of therapy. The

demographic characteristics of women on the trial with follow-up data are shown in Table 2.

Table 2: Demographic Characteristics

of Women in the NSABP P-1 Trial

Characteris tic

Placebo

Tamoxifen

#

%

#

%

Age (yrs.)

35 to 39

40 to 49

2,394

2,411

50 to 59

2,011

2,019

60 to 69

1,588

1,563

≥70

Age at first live birth (yrs.)

Nulliparous

1,202

1,205

12 to 19

20 to 24

2,448

2,449

25 to 29

1,399

1,367

≥30

Race

White

6,333

6,323

Black

Other

Age at menarche

≥14

1,243

1,170

12 to 13

3,610

3,610

≤11

1,717

1,764

# of first degree relatives with breast

cancer

1,584

1,525

3,714

3,744

1,272

1,275

Prior Hysterectomy

4,173 63.5 4,018 62.4

2,397 36.5 2,464 37.7

# of previous breast biopsies

2,935

2,923

1,833

1,850

≥2

1,802

1,771

History of atypical hyperplasia in the

breast

5,958

5,969

History of LCIS at entry

6,165

6,135

5-year predicted breast cancer risk (%)

≤2.00

1,646

1,626

2.01 to 3.00

2,028

2,057

3.01 to 5.00

1,787

1,707

≥5.01

1,109

1,162

Total

6,570 100.0 6,544 100.0

Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast

cancer was reduced by 44% among women assigned to tamoxifen (86 cases-tamoxifen, 156 cases-

placebo; p less than 0.00001; relative risk (RR)=0.56, 95% CI: 0.43 to 0.72). A reduction in the

incidence of breast cancer was seen in each prospectively specified age group (less than or equal to

49, 50 to 59, greater than or equal to 60), in women with or without LCIS, and in each of the absolute

risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ

(DCIS) was seen (23-tamoxifen, 35-placebo; RR=0.66; 95% CI: 0.39 to 1.11).

There was no statistically significant difference in the number of myocardial infarctions, severe angina,

or acute ischemic cardiac events between the two groups (61-tamoxifen citrate, 59- placebo; RR=1.04,

95% CI: 0.73 to 1.49).

No overall difference in mortality (53 deaths in tamoxifen group vs. 65 deaths in placebo group) was

present. No difference in breast cancer-related mortality was observed (4 deaths in tamoxifen group vs.

5 deaths in placebo group).

Although there was a non-significant reduction in the number of hip fractures (9 on tamoxifen, 20 on

placebo) in the tamoxifen group, the number of wrist fractures was similar in the two treatment groups

(69 on tamoxifen, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect

in bone mineral density (BMD) related to menopausal status in patients receiving tamoxifen. In

postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely,

tamoxifen citrate was associated with significant bone loss of the lumbar spine and hip in premenopausal

women.

The risks of tamoxifen therapy include endometrial cancer, DVT, PE, stroke, cataract formation, and

cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed

in the tamoxifen group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27 to 4.92). Deep-vein

thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo

(RR=1.59, 95% CI: 0.86 to 2.98). Eighteen cases of pulmonary embolism were observed in the

tamoxifen group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15 to 9.27). There were 34 strokes on

the tamoxifen arm and 24 on the placebo arm (RR=1.42; 95% CI: 0.82 to 2.51). Cataract formation in

women without cataracts at baseline was observed in 540 women taking tamoxifen vs. 483 women

receiving placebo (RR=1.13, 95% CI: 1.00 to 1.28). Cataract surgery (with or without cataracts at

baseline) was performed in 201 women taking tamoxifen vs. 129 women receiving placebo (RR=1.51,

95% CI: 1.21 to 1.89) (see WARNINGS).

Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following

results are presented: the number of events and rate per 1000 women per year for the placebo and

tamoxifen groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between

tamoxifen and placebo. Relative risks less than 1.0 indicate a benefit of tamoxifen therapy. The limits of

the confidence intervals can be used to assess the statistical significance of the benefits or risks of

tamoxifen therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit

exists.

For most participants, multiple risk factors would have been required for eligibility. This table

considers risk factors individually, regardless of other co-existing risk factors, for women who

developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk

factors in an individual and should provide the best estimate of individual benefit (see INDICATIONS

AND USAGE).

Table 3: Major Outcomes of the NSABP P-1 Trial

# Of Events

Rate/1000 Women/Year

RR

95% CI

LIMITS

Type of Event

Placebo

Tamoxifen

Placebo

Tamoxifen

Invasive Breast Cancer

6.49

3.58

0.56

0.43 to

0.72

Age ≤49

6.34

4.11

0.65

0.43 to

0.98

Age 50 to 59

6.31

3.53

0.56

0.35 to

0.91

Age ≥60

7.17

3.22

0.45

0.27 to

0.74

Risk Factors for Breast Cancer History, LCIS

6.23

3.51

0.56

0.43 to

0.74

12.73

6.33

0.50

0.21 to

1.17

History, Atypical Hyperplasia

6.37

3.89

0.61

0.47 to

0.80

8.69

1.05

0.12

0.03 to

0.52

No. First Degree Relatives

5.97

3.26

0.55

0.30 to

0.98

5.81

3.31

0.57

0.40 to

0.82

8.92

4.67

0.52

0.30 to

0.92

≥3

13.33

7.58

0.57

0.20 to

1.59

5-Year Predicted Breast Cancer Risk (as calculated by the Gail Model)

≤2.00%

5.36

2.26

0.42

0.22 to

0.81

2.01 to 3.00%

5.25

3.83

0.73

0.45 to

1.18

3.01 to 5.00%

5.37

4.06

0.76

0.46 to

1.26

≥5.00%

13.15

4.71

0.36

0.21 to

0.61

DCIS

1.47

0.97

0.66

0.39 to

DCIS

1.47

0.97

0.66

1.11

Fractures (protocol-

specified sites)

3.87

3.20

0.61

0.83 to

1.12

0.84

0.38

0.45

0.18 to

1.04

Wrist

3.11

2.91

0.93

0.67 to

1.29

Total Ischemic Events

2.47

2.57

1.04

0.71 to

1.51

Myocardial Infarction

1.13

1.13

1.00

0.57 to

1.78

Fatal

0.33

0.29

0.88

0.27 to

2.77

Nonfatal

0.79

0.84

1.06

0.54 to

2.09

Angina

0.50

0.50

1.00

0.41 to

2.44

Acute Ischemic Syndrome

0.84

0.92

1.11

0.58 to

2.13

Uterine

Malignancies (among

women with an intact

uterus )

Endometrial Adenocarcinoma

0.71

2.20

Uterine Sarcoma

0.17

Stroke

1.00

1.43

1.42

0.82 to

2.51

Transient Ischemic Attack

0.88

0.75

0.86

0.43 to

1.70

Pulmonary Emboli

0.25

0.75

3.01

1.15 to

9.27

Deep-Vein Thrombosis

0.79

1.26

1.59

0.86 to

2.98

Cataracts Developing on

Study

22.51

25.41

1.13

1.00 to

1.28

Underwent Cataract

Surgery

2.83

4.57

1.62

1.18 to

2.22

Underwent Cataract

Surgery

5.44

8.56

1.58

1.26 to

1.97

Two women had hip and wrist fractures

Includes Colles' and other lower radius fractures

Requiring angioplasty or CABG

New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization

without surgery

Seven cases were fatal; three in the placebo group and four in the tamoxifen group

Three cases in the tamoxifen group were fatal

10

6

7

8

8

9

All but three cases in each group required hospitalization

Based on women without cataracts at baseline (6,230-Placebo, 6,199-tamoxifen)

All women (6,707-Placebo, 6,681-tamoxifen)

Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study added after cut-off for

the other information in this table.

Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor

size, nodal status, ER status. Tamoxifen decreased the incidence of small estrogen receptor positive

tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors.

Table 4: Characteristics of Breast Cancer

in NSABP P-1 Trial

Staging

Parameter

Placebo

N=156

Tamoxifen

N=86

Total

N=242

Tumor Size:

Unknown

Nodal Status:

Negative

1 to 3 positive

nodes

≥ 4 positive

nodes

Unknown

Stage:

II: node negative

II: node positive

Unknown

Estrogen

receptor:

Positive

Negative

Unknown

One participant presented with a suspicious bone scan but did not have documented metastases. She

subsequently died of metastatic breast cancer.

Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in

reducing breast cancer incidence have been reported.

The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70,

who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo

for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women

without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5408

women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The

trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After

46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on

tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for a

reduction in breast cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11-

tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy

group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast

cancer.

The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was

begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was

subsequently extended to a pilot trial to accrue additional participants to further assess the safety of

tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they

were selected on the basis of a family history of breast cancer. HRT was used in 40% of participants.

In this trial, with a 70-month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm)

were observed among women on tamoxifen and placebo, respectively. Patients in this trial were

younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors,

which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on

the basis of family history and were thought to have a high risk of breast cancer, few events occurred,

reducing the statistical power of the study. These factors are potential reasons why the RMT may not

have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of

breast cancer.

In these trials, an increased number of cases of deep-vein thrombosis, pulmonary embolus, stroke, and

endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of

events was consistent with the safety data observed in the NSABP P-1 trial.

McCune-Albright Syndrome:

A single, uncontrolled multicenter trial of tamoxifen 20 mg once a day was conducted in a heterogenous

group of girls with McCune-Albright syndrome and precocious puberty manifested by physical signs

of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least

12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were

treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age

advancement, and linear growth rate was assessed relative to prestudy baseline. Tamoxifen treatment

was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family

report (mean annualized frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among

the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients)

reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding

for the duration of the trial. Not all patients improved on treatment and a few patients not reporting

vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen therapy

was associated with a reduction in mean rate of increase of bone age. Individual responses with regard

to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the

course of tamoxifen treatment in a majority of patients (mean change of 1.68 cm/year relative to

baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not

uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients

with bone ages less than 7 years at screening.

Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study.

A causal relationship has not been established; however, as an increase in the incidence of endometrial

adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen (see BOXED

WARNING), continued monitoring of McCune-Albright patients treated with tamoxifen for long-term

uterine effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years

with McCune-Albright syndrome and precocious puberty have not been studied beyond one year

of treatment. The long-term effects of tamoxifen therapy in girls have not been established.

INDICATIONS AND USAGE

Metastatic Breast Cancer:

Tamoxifen citrate tablets, USP are effective in the treatment of metastatic breast cancer in women and

men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to

oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are

estrogen receptor positive are more likely to benefit from tamoxifen therapy.

Adjuvant Treatment of Breast Cancer:

Tamoxifen citrate tablets, USP are indicated for the treatment of node-positive breast cancer in women

following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some

tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more

positive axillary nodes.

Tamoxifen citrate tablets, USP are indicated for the treatment of axillary node-negative breast cancer in

women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation.

The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy

is likely to be beneficial.

Tamoxifen reduces the occurrence of contralateral breast cancer in patients receiving adjuvant

tamoxifen therapy for breast cancer.

Ductal Carcinoma in Situ (DCIS):

In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to

reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The

decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based

upon an individual assessment of the benefits and risks of tamoxifen therapy.

Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast

cancer.

Reduction in Breast Cancer Incidence in High Risk Women:

Tamoxifen citrate tablets are indicated to reduce the incidence of breast cancer in women at high risk

for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up

of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects

are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related

mortality (see BOXED WARNING at the beginning of the label).

Tamoxifen citrate tablets are indicated only for high-risk women. “High risk” is defined as women at

least 35 years of age with a 5-year predicted risk of breast cancer greater than or equal to 1.67%, as

calculated by the Gail Model.

Examples of combinations of factors predicting a 5-year risk greater than or equal to 1.67% are:

Age 35 or older and any of the following combination of factors:

One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of

a breast biopsy showing atypical hyperplasia; or

At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one

breast biopsy; or

LCIS

Age 40 or older and any of the following combination of factors:

One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live

birth 25 or older, and age at menarche 11 or younger; or

At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or

younger; or

One first degree relative with a history of breast cancer, and a personal history of a breast biopsy

showing atypical hyperplasia.

Age 45 or older and any of the following combination of factors:

At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or

younger; or

One first degree relative with a history of breast cancer with a personal history of a benign breast

biopsy, age at menarche 11 or less and age at first live birth 20 or more.

Age 50 or older and any of the following combination of factors:

At least 2 first degree relatives with a history of breast cancer; or

History of 1 breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and

age at menarche 11 or less; or

History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth

30 or more.

Age 55 or older and any of the following combination of factors:

One first degree relative with a history of breast cancer with a personal history of a benign breast

biopsy, and age at menarche 11 or less; or

History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth

20 or older.

Age 60 or older and:

Five-year predicted risk of breast cancer greater than or equal to 1.67%, as calculated by the Gail

Model.

For women whose risk factors are not described in the above examples, the Gail Model is necessary to

estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk

Assessment Tool by dialing 1-800-272-5525.

There are insufficient data available regarding the effect of tamoxifen on breast cancer incidence in

women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the

effectiveness of tamoxifen citrate in these patients.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with

tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of

the benefits and risks of tamoxifen citrate therapy. In the NSABP P-1 trial, tamoxifen treatment lowered

the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast

cancer risk (see Table 3 in CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

Tamoxifen citrate tablets are contraindicated in patients with known hypersensitivity to the drug or any

of its ingredients.

Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS:

Tamoxifen citrate tablets are contraindicated in women who require concomitant coumarin-type

anticoagulant therapy or in women with a history of deep-vein thrombosis or pulmonary embolus.

WARNINGS

Effects in Metastatic Breast Cancer Patients:

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. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen

should be discontinued.

Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma:

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 tumors (MMMT), 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 (greater than or equal to 2 years) of

tamoxifen citrate than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine

sarcoma) have been fatal.

In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant

increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to

14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27 to 4.92). The 33 cases in

participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial

adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1

was FIGO Stage IV. Five women on tamoxifen citrate and 1 on placebo received postoperative radiation

therapy in addition to surgery. This increase was primarily observed among women at least 50 years of

age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among

participants randomized to placebo (RR=4.50, 95% CI: 1.78 to 13.16). Among women less than or equal

to 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer,

compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28 to 2.89). If age

at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants less

than or equal to 49 randomized to tamoxifen compared to 2 among participants randomized to placebo

(RR=2.21, 95% CI: 0.4 to 12.0). For women greater than or equal to 50 at the time of diagnosis, there

were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo

(RR=2.5, 95% CI: 1.3 to 4.9). The risk ratios were similar in the two groups, although fewer events

occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were

diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in

asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months

(average=32 months) from the start of treatment.

In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded

follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial,

the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking

tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma

(22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women

receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the

patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB

cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer

received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and

hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women

randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were

Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was

Stage IIIC, and 1 was Stage IVB) (incidence per 1000 women-years of 2.20 and 0.71, respectively).

Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were

reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1

was FIGO IIIC) and 1 patient randomized to placebo (FIGO 1A); incidence per 1000 women-years of

0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a

MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the

1 patient randomized to placebo had a MMMT. A similar increased incidence in endometrial

adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other

NSABP clinical trials.

Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding

should be promptly evaluated. Patients receiving or who have previously received tamoxifen should

have annual gynecological examinations and they should promptly inform their physicians if they

experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal

bleeding, changes in vaginal discharge, or pelvic pain or pressure.

In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to

women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for

women with an intact uterus. There are no data to suggest that routine endometrial sampling in

asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial.

Non-Malignant Effects on the Uterus:

An increased incidence of endometrial changes including hyperplasia and polyps has been reported in

association with tamoxifen treatment. The incidence and pattern of this increase suggest that the

underlying mechanism is related to the estrogenic properties of tamoxifen.

There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen.

The underlying mechanism may be due to the partial estrogenic effect of tamoxifen. Ovarian cysts have

also been observed in a small number of premenopausal patients with advanced breast cancer who have

been treated with tamoxifen.

Tamoxifen has been reported to cause menstrual irregularity or amenorrhea.

Thromboembolic Effects of Tamoxifen:

There is evidence of an increased incidence of thromboembolic events, including deep-vein thrombosis

and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered 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. In a small substudy (N=81) of the NSABP P-1 trial, there

appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A

as a means to identify those who may not be appropriate candidates for tamoxifen therapy.

Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of

pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-tamoxifen, 6-

placebo; RR=3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were

fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of

age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months

(average = 27 months) from the start of treatment.

In this same population, a non-statistically significant increase in deep-vein thrombosis (DVT) was seen

in the tamoxifen group (30-tamoxifen, 19-placebo; RR=1.59, 95% CI: 0.86 to 2.98). The same increase

in relative risk was seen in women less than or equal to 49 and in women greater than or equal to 50,

although fewer events occurred in younger women. Women with thromboembolic events were at risk

for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at

risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen). Among

women receiving tamoxifen, deep-vein thrombosis events occurred between 2 and 57 months (average =

19 months) from the start of treatment.

There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24-

Placebo; 34-tamoxifen; RR=1.42; 95% CI: 0.82 to 2.51). Six of the 24 strokes in the placebo group

were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were

categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered

occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo

arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the

placebo group and 4 strokes in the tamoxifen group were fatal. Eighty-eight percent of the strokes

occurred in women at least 50 years of age at the time of randomization. Among women receiving

tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of

treatment.

Effects on the Liver: Liver Cancer:

In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2 to 5 years, 3 cases of liver cancer have

been reported in the tamoxifen-treated group vs. 1 case in the observation group (see

PRECAUTIONS, Carcinogenesis). In other clinical trials evaluating tamoxifen, no cases of liver

cancer have been reported to date.

One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen.

Effects on the Liver: Non-Malignant Effects:

Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum

of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A

few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is

uncertain. However, some positive rechallenges and dechallenges have been reported.

In the NSABP P-1 trial, few grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline

phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically

collected.

Other Cancers:

A number of second primary tumors, occurring at sites other than the endometrium, have been reported

following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14

and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen.

Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain

and continues to be evaluated.

Effects on the Eye:

Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein

thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence

of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen.

In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among

those women without cataracts at baseline (540-tamoxifen; 483-placebo; RR=1.13, 95% CI: 1.00 to

1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of

having cataract surgery (101-tamoxifen; 63-placebo; RR=1.62, 95% CI: 1.18 to 2.22) (see Table 3 in

CLINICAL PHARMACOLOGY). Among all women on the trial (with or without cataracts at

baseline), tamoxifen was associated with an increased risk of having cataract surgery (201-tamoxifen;

129-placebo; RR=1.58, 95% CI: 1.26 to 1.97). Eye examinations were not required during the study. No

other conclusions regarding non-cataract ophthalmic events can be made.

Pregnancy Category D:

Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not

to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should

use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause

infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are

expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels

equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were

found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at

or below those used in humans, a lower incidence of embryo implantation and a higher incidence of

fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups

when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day

(about 2-fold the daily maximum recommended human dose on a mg/m

basis) during organogenesis or

in the last half of pregnancy. No deformations were seen and, although the dose was high enough to

terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of

teratogenic malformations.

In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold the daily

maximum recommended human dose on a mg/m

basis) caused changes in both sexes that are similar to

those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of

these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen

in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1000 risk of

developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen

has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in

young women. However, only a small number of young women have been exposed to tamoxifen in utero,

and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or

cervical neoplasia could occur as a result of this exposure.

There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a

small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in

pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this

drug, or within approximately two months after discontinuing therapy, the patient should be apprised of

the potential risks to the fetus including the potential long-term risk of a DES-like syndrome.

Reduction in Breast Cancer Incidence in High Risk Women

Pregnancy Category D:

For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during

menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation

of therapy is sufficient (see PRECAUTIONS, Information for Patients, Reduction in Breast Cancer

Incidence in High Risk Women).

PRECAUTIONS

General:

Decreases in platelet counts, usually to 50,000 to 100,000/mm

, infrequently lower, have been

occasionally reported in patients taking tamoxifen for breast cancer. In patients with significant

thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are

due to tamoxifen therapy. Leukopenia has been observed, sometimes in association with anemia and/or

thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving

tamoxifen; this can sometimes be severe.

In the NSABP P-1 trial, 6 women on tamoxifen citrate and 2 on placebo experienced grade 3 to 4 drops

in platelet counts (less than or equal to 50,000/mm

Information for Patients:

Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen

citrate is dispensed. The complete text of the Medication Guide is reprinted at the end of this document.

Reduction in Invasive Breast Cancer and DCIS in Women with DCIS: Women with DCIS treated with

lumpectomy and radiation therapy who are considering tamoxifen to reduce the incidence of a second

breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen

decreased the incidence of invasive breast cancer, but has not been shown to affect survival (see Table

1 in CLINICAL PHARMACOLOGY).

Reduction in Breast Cancer Incidence in High Risk Women: Women who are at high risk for breast cancer

can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of

treatment are considered to outweigh the risks depends on a woman's personal health history and on how

she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may

therefore not be appropriate for all women at high risk for breast cancer. Women who are considering

tamoxifen therapy should consult their health care professional for an assessment of the potential

benefits and risks prior to starting therapy for reduction in breast cancer incidence (see Table 3 in

CLINICAL PHARMACOLOGY). Women should understand that tamoxifen reduces the incidence of

breast cancer, but may not eliminate risk. Tamoxifen decreased the incidence of small estrogen receptor

positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In

women with breast cancer who are at high risk of developing a second breast cancer, treatment with

about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately

50%.

Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce their risk

of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking

tamoxifen and for approximately two months after discontinuing therapy if they are sexually active.

Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active

women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women

with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient

(see WARNINGS, Pregnancy Category D).

Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no

difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies

had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled

women at a lower risk for breast cancer than those in P-1.

Monitoring During Tamoxifen Citrate Therapy: Women taking or having previously taken tamoxifen

should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding,

gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or

pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in

vision. Women should inform all care providers, regardless of the reason for evaluation, that they take

tamoxifen.

Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a

mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be

repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking

tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for

women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as

treatment for metastatic breast cancer should review this monitoring plan with their care provider and

select the appropriate modalities and schedule of evaluation.

Laboratory Tests:

Periodic complete blood counts, including platelet counts, and periodic liver function tests should be

obtained.

During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum

cholesterol compared to patients receiving tamoxifen citrate (9% versus 3.5%, respectively).

Drug Interactions:

When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in

anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's

prothrombin time is recommended.

In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were

ineligible for participation in the trial (see CONTRAINDICATIONS).

There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in

combination with tamoxifen.

Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and

excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed

function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma

concentrations have been shown to be reduced when coadministered with rifampin or

aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by

which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this

effect.

One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady-state serum level of

tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL).

However, the clinical significance of this finding is not known. Rifampin induced the metabolism of

tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients.

Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations.

Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl

tamoxifen.

Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, tamoxifen citrate

should not be administered with anastrozole (see CLINICAL PHARMACOLOGY, Drug-Drug

Interactions ).

Drug/Laboratory Testing Interactions:

During postmarketing surveillance, T

elevations were reported for a few postmenopausal patients

which may be explained by increases in thyroid-binding globulin. These elevations were not

accompanied by clinical hyperthyroidism.

Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap

smears have been infrequently seen in postmenopausal patients given tamoxifen.

In the postmarketing experience with tamoxifen, infrequent cases of hyperlipidemias have been

reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with

pre-existing hyperlipidemias (see ADVERSE REACTIONS, Postmarketing Experience).

Carcinogenes is :

A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and

seven-fold the daily maximum recommended human dose on a mg/m

basis) administered by oral gavage

for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence

of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared

to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45

mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m

basis);

hepatocellular neoplasia was exhibited at 3 to 6 months.

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in 2 separate mouse

studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at

doses of 5, 20 and 50 mg/kg/day (about one-half, two, and five-fold the daily recommended human dose

on a mg/m

basis).

Mutagenes is :

No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and

eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts

were observed by

P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen

also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell

line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.

Impairment of Fertility:

Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day

(about 0.01-fold the daily maximum recommended human dose on a mg/m

basis) when dosed for two

weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were

markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16

mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m

basis) when

female rats were dosed from days 7 to 17 of pregnancy. Tamoxifen produced abortion, premature

delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about

0.05-fold the daily maximum recommended human dose on a mg/m

basis). There were no teratogenic

changes in either rats or rabbits.

Pregnancy

Teratogenic Effects

Pregnancy Category D

See WARNINGS.

Nursing Mothers:

Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women

have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies

tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of

tamoxifen on established milk production is not known.

There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no

data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals.

However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1)

reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure

to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular

atrophy and arrest of spermatogenesis.

It is not known if tamoxifen citrate is excreted in human milk. Because of the potential for serious

adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed.

Reduction in Breast Cancer Incidence in High Risk Women With DCIS:

It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse

reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed.

Pediatric Use:

The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome

and precocious puberty have not been studied beyond one year of treatment. The long-term

effects of tamoxifen therapy for girls have not been established. In adults treated with tamoxifen, an

increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see

BOXED WARNING and CLINICAL PHARMACOLOGY, Clinical Studies, McCune-Albright

Syndrome subsection).

Geriatric Use:

In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70

years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen

among participants in each of the subsets. A total of 28 and 10 invasive breast cancers were seen among

participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes,

the results in this subset reflect the results observed in the subset of women at least 50 years of age. No

overall differences in tolerability were observed between older and younger patients (see CLINICAL

PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence in High Risk Women).

In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70

years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen

among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too

small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were

comparable to those of younger women enrolled in this trial. No overall differences in tolerability

were observed between older and younger patients.

ADVERSE REACTIONS

Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation

of treatment in breast cancer patients.

Continued clinical studies have resulted in further information which better indicates the incidence of

adverse reactions with tamoxifen as compared to placebo.

Metastatic Breast Cancer:

Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes

associated with a good tumor response. Patients with increased bone pain may require additional

analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting

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 tamoxifen and generally subside rapidly.

In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to

tamoxifen is hot flashes.

Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for

food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial

hair loss, and vaginal dryness.

Premenopausal Women:

The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or

greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen therapy to ovarian

ablation in premenopausal patients with metastatic breast cancer.

TAMOXIFEN

All Effects

% of Women

OVARIAN

ABLATION

All Effects

% of

Women

Adverse

Reactions *

n=104

n=100

Flush

Amenorrhea

Altered Menses

Oligomenorrhea

Bone Pain

Menstrual

Disorder

Nausea

Cough/Coughing

Edema

Fatigue

Musculoskeletal

Pain

Pain

Ovarian Cyst(s)

Depression

Abdominal Cramps

Anorexia

*Some women had more than one adverse reaction.

Male Breast Cancer:

Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports

suggest that the safety profile of tamoxifen in males is similar to that seen in women. Loss of libido and

impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic

males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant

clinical changes were reported.

Adjuvant Breast Cancer:

In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years

of tamoxifen 20 mg/day or placebo following primary surgery. The reported adverse effects are

tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on

tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs.

15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All

other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of

thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs.

0.4%). Two of the patients treated with tamoxifen who had thrombotic events died.

NSABP B-14 Study

% of Women

Adverse Effect

TAMOXIFEN

(n=1422)

PLACEBO

(n=1437)

Hot Flashes

Fluid Retention

Vaginal Discharge

Nausea

Irregular Menses

Weight Loss

(>5%)

Skin Changes

Increased SGOT

Increased

Bilirubin

Increased

Creatinine

Thrombocytopenia

Thrombotic Events

Deep Vein

Thrombosis

Pulmonary

Embolism

Superficial

Phlebitis

*Defined as a platelet count of less than 100,000/mm

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo

was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen

showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all

other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia

where the incidence for tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical

significance.

In other adjuvant studies, Toronto and Tamoxifen Adjuvant Trial Organization (NATO), women

received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of

patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding

were reported in 2.8%, and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the

untreated group.

Anastrozole Adjuvant Trial - Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of

Early Breast Cancer (see CLINICAL PHARMACOLOGY, Clinical Studies).

At a median follow-up of 33 months, the combination of anastrozole and tamoxifen citrate did not

demonstrate any efficacy benefit when compared to tamoxifen therapy given alone in all patients as well

as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial.

The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for

patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively.

Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or

within 14 days of the end of treatment are presented in the following table.

Adverse events occurring with an incidence of at least 5% in either treatment group during

treatment, or within 14 days of the end of treatment

Body system and adverse event by

COSTART-preferred term*

Anas trozole

1 mg

(N = 3092)

TAMOXIFEN

20 mg

(N = 3094)

Body as a whole

Asthenia

575 (19)

544 (18)

Pain

533 (17)

485 (16)

Back pain

321 (10)

309 (10)

Headache

314 (10)

249 (8)

Abdominal pain

271 (9)

276 (9)

Infection

285 (9)

276 (9)

Accidental injury

311 (10)

303 (10)

Flu syndrome

175 (6)

195 (6)

Chest pain

200 (7)

150 (5)

Neoplasm

162 (5)

144 (5)

Cyst

138 (5)

162 (5)

Cardiovascular

Vasodilatation

1104 (36)

1264 (41)

Hypertension

402 (13)

349 (11)

Digestive

Nausea

343 (11)

335 (11)

Constipation

249 (8)

252 (8)

Diarrhea

265 (9)

216 (7)

Dyspepsia

206 (7)

169 (6)

Gastrointestinal disorder

210 (7)

158 (5)

Hemic and lymphatic

Lymphoedema

304 (10)

341 (11)

Anemia

113 (4)

159 (5)

Metabolic and nutritional

Peripheral edema

311 (10)

343 (11)

Weight gain

285 (9)

274 (9)

Hypercholesterolemia

278 (9)

108 (3.5)

Musculoskeletal

Arthritis

512 (17)

445 (14)

Arthralgia

467 (15)

344 (11)

Osteoporosis

325 (11)

226 (7)

Fracture

315 (10)

209 (7)

Bone pain

201 (7)

185 (6)

Arthrosis

207 (7)

156 (5)

Joint Disorder

184 (6)

160 (5)

Myalgia

179 (6)

160 (5)

Nervous system

Depression

413 (13)

382 (12)

Insomnia

309 (10)

281 (9)

Dizziness

236 (8)

234 (8)

Anxiety

195 (6)

180 (6)

Paraesthesia

215 (7)

145 (5)

Respiratory

Pharyngitis

443 (14)

422 (14)

Cough increased

261 (8)

287 (9)

Dyspnea

234 (8)

237 (8)

Sinusitis

184 (6)

159 (5)

Bronchitis

167 (5)

153 (5)

Skin and appendages

Rash

333 (11)

387 (13)

Sweating

145 (5)

177 (6)

Special Senses

Cataract specified

182 (6)

213 (7)

Urogenital

Leukorrhea

86 (3)

286 (9)

Urinary tract infection

244 (8)

313 (10)

Breast pain

251 (8)

169 (6)

Breast neoplasm

164 (5)

139 (5)

Vulvovaginitis

194 (6)

150 (5)

Vaginal hemorrhage†

122 (4)

180 (6)

Vaginitis

125 (4)

158 (5)

COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.

N = Number of patients receiving the treatment.

*A patient may have had more than 1 adverse event, including more than 1 adverse event in the same

body system.

† Vaginal hemorrhage without further diagnosis.

** The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.

Certain adverse events and combinations of adverse events were prospectively specified for analysis,

based on the known pharmacologic properties and side effect profiles of the two drugs (see the

following table).

Number (%) of Patients with Pre-Specified Adverse Event in the Anastrozole Adjuvant Trial

Anas trozole

N=3092

(%)

TAMOXIFEN

N=3094

(%)

Odds-ratio

95% Cl

Hot Flashes

1104 (36)

1264 (41)

0.80

0.73 to 0.89

Musculoskeletal Events

1100 (36)

911 (29)

1.32

1.19 to 1.47

Fatigue/Asthenia

575 (19)

544 (18)

1.07

0.94 to 1.22

Mood Disturbances

597 (19)

554 (18)

1.10

0.97 to 1.25

Nausea and Vomiting

393 (13)

384 (12)

1.03

0.88 to 1.19

All Fractures

315 (10)

209 (7)

1.57

1.30 to 1.88

Fractures of Spine, Hip, or

Wrist

133 (4)

91 (3)

1.48

1.13 to 1.95

Wrist/Colles’ fractures

67 (2)

50 (2)

Spine fractures

43 (1)

22 (1)

Hip fractures

28 (1)

26 (1)

Cataracts

182 (6)

213 (7)

0.85

0.69 to 1.04

Vaginal Bleeding

167 (5)

317 (10)

0.50

0.41 to 0.61

Ischemic Cardiovascular

Disease

127 (4)

104 (3)

1.23

0.95 to 1.60

Vaginal Discharge

109 (4)

408 (13)

0.24

0.19 to 0.30

Venous Thromboembolic

events

87 (3)

140 (5)

0.61

0.47 to 0.80

Deep Venous

Thromboembolic Events

48 (2)

74 (2)

0.64

0.45 to 0.93

Ischemic Cerebrovascular

Event

62 (2)

88 (3)

0.70

0.50 to 0.97

1

4

4

Endometrial Cancer

4 (0.2)

13 (0.6)

0.31

0.10 to 0.94

Patients with multiple events in the same category are counted only once in that category.

Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.

Percentages calculated based upon the numbers of patients with an intact uterus at baseline.

The odds ratios < 1.00 favor Anastrozole and those > 1.00 favor tamoxifen.

Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and

arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in

the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with

patients receiving tamoxifen [209 (7%)]. Patients receiving anastrozole had a decrease in hot flashes,

vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic

cerebrovascular events compared with patients receiving tamoxifen.

Patients receiving tamoxifen had a decrease in hypercholesterolemia (108 [3.5%]) compared to patients

receiving anastrozole (278 [9%]). Angina pectoris was reported in 71 [2.3%] patients in the anastrozole

arm and 51 [1.6%] patients in the tamoxifen arm; myocardial infarction was reported in 37 [1.2%] patients

in the anastrozole arm and in 34 [1.1%] patients in the tamoxifen arm.

Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving

anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD)

compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total

hip BMD compared to baseline.

Ductal Carcinoma in Situ (DCIS):

The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed

in the other adjuvant trials conducted with tamoxifen.

Reduction in Breast Cancer Incidence in High Risk Women:

In the NSABP P-1 trial, there was an increase in five serious adverse effects in the tamoxifen group:

endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism

(18 cases in the tamoxifen group vs. 6 in the placebo group); deep-vein thrombosis (30 cases in the

tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the

placebo group); cataract formation (540 cases in the tamoxifen citrate group vs. 483 in the placebo

group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group) (See

WARNINGS and Table 3 in CLINICAL PHARMACOLOGY).

The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only

adverse events more common on tamoxifen than placebo are shown.

NSABP P-1 Trial: All Adverse Events

% of Women

TAMOXIFEN

N=6681

PLACEBO

N=6707

Self Reported

Symptoms

N=6441

N=6469

Hot Flashes

Vaginal Discharges

Vaginal Bleeding

Laboratory

Abnormalities

N=6520

N=6535

Platelets decreased

Adverse Effects

N=6492

N=6484

Other Toxicities

Mood

11.6

10.8

Infection/Sepsis

Constipation

Alopecia

Skin

Allergy

Number with Quality of Life Questionnaires

Number with Treatment Follow-up Forms

Number with Adverse Drug Reaction Forms

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy,

respectively withdrew from the trial for medical reasons. The following are the medical reasons for

withdrawing from tamoxifen and placebo therapy, respectively: hot flashes (3.1% vs. 1.5%) and vaginal

discharge (0.5% vs. 0.1%).

In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen citrate and placebo therapy,

respectively withdrew for non-medical reasons.

On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80%

of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women

on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen

respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence

of vaginal bleeding between treatment arms.

Pediatric Patients

McCune-Albright Syndrome:

Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study.

A causal relationship has not been established; however, as an increase in the incidence of endometrial

adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen (see BOXED

WARNING), continued monitoring of McCune-Albright patients treated with tamoxifen for long-term

effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with

McCune-Albright syndrome and precocious puberty have not been studied beyond 1 year of

treatment. The long-term effects of tamoxifen therapy in girls have not been established.

Postmarketing Experience:

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual

irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require

dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-

Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity

reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the

time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with

pancreatitis, may be associated with the use of tamoxifen (see PRECAUTIONS, Drug/Laboratory

Testing Interactions).

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-272-5525 or FDA at 1-

800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

OVERDOSAGE

Signs observed at the highest doses following studies to determine LD

in animals were respiratory

difficulties and convulsions.

Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients

which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very

high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia,

unsteady gait and dizziness were noted. These symptoms occurred within 3 to 5 days of beginning

tamoxifen and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was

noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic

symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses

given in these patients were all greater than 400 mg/m

loading dose, followed by maintenance doses

of 150 mg/m

of tamoxifen given twice a day.

In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients

were given doses higher than 250 mg/m

loading dose, followed by maintenance doses of 80 mg/m

tamoxifen given twice a day. For a woman with a body surface area of 1.5 m

the minimal loading dose

and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6

fold higher in respect to the maximum recommended dose.

No specific treatment for overdosage is known; treatment must be symptomatic.

DOSAGE AND ADMINISTRATION

For patients with breast cancer, the recommended daily dose is 20 to 40 mg. Dosages greater than 20

mg per day should be given in divided doses (morning and evening).

In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two

(ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in

women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for

at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does

not provide additional benefit (see CLINICAL PHARMACOLOGY). In the EBCTCG 1995

overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for

about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication

that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5

years of adjuvant tamoxifen therapy for patients with breast cancer.

Ductal Carcinoma in Situ (DCIS):

The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women:

The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years. There are no data to support

the use of tamoxifen other than for 5 years (see CLINICAL PHARMACOLOGY, Clinical Studies,

Reduction in Breast Cancer Incidence in High Risk Women).

HOW SUPPLIED

20 mg: Containing 30.4 mg tamoxifen citrate, an amount equivalent to 20 mg of tamoxifen. White, round,

unscored, biconvex tablet. Debossed with 2233 on one side and WPI on the other side.

NDC 68071-5005-3 BOTTLES OF 30

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a well-closed, light-resistant container.

For more information about tamoxifen citrate, call 1-800-272-5525.

Arimidex® is a trademark of AstraZeneca.

MEDICATION GUIDE

Tamoxifen Citrate Tablets, USP

(ta-MOX-I-fen)

Written for women who use tamoxifen to lower their high chance of getting breast cancer or who have ductal

carcinoma in situ (DCIS)

This Medication Guide discusses only the use of tamoxifen to lower the chance of getting breast

cancer in high-risk women and in women treated for DCIS.

People taking tamoxifen to treat breast cancer have different benefits and different decisions to make

than high-risk women or women with ductal carcinoma in situ (DCIS) taking tamoxifen to reduce the

chance of getting breast cancer. If you already have breast cancer, talk with your doctor about how the

benefits of treating breast cancer with tamoxifen compare to the risks that are described in this

document.

Why should I read this Medication Guide?

This guide has information to help you decide whether to use tamoxifen to lower your chance of

getting breast cancer.

You and your doctor should talk about whether the possible benefit of tamoxifen in lowering your

high chance of getting breast cancer is greater than its possible risks. Your doctor has a special

computer program or hand-held calculator to tell if you are in the high-risk group. If you have DCIS

and have been treated with surgery and radiation therapy, your doctor may prescribe tamoxifen to

decrease your chance of getting invasive (spreading) breast cancer.

Read this guide carefully before you start tamoxifen. It is important to read the information you get each

time you get more medicine. There may be something new. This guide does not tell you everything

about tamoxifen and does not take the place of talking with your doctor.

Only you and your doctor can determine if tamoxifen is right for you.

What is the most important information I should know about using tamoxifen to reduce the

chance of getting breast cancer?

Tamoxifen is a prescription medicine that is like estrogen (female hormone) in some ways and different

in other ways. In the breast, tamoxifen can block estrogen’s effects. Because it does this, tamoxifen may

block the growth of breast cancers that need estrogen to grow (cancers that are estrogen- or

progesterone-receptor positive).

Tamoxifen can lower the chance of getting breast cancer in women with a higher than normal chance of

getting breast cancer in the next five years (high-risk women) and women with DCIS.

Because high-risk women don’t have cancer yet, it is important to think carefully about whether

the possible benefit of tamoxifen in lowering the chance of getting breast cancer is greater than

its possible risks.

This Medication Guide reviews the risks and benefits of using tamoxifen to reduce the chance of

getting breast cancer in high-risk women and women with DCIS. This guide does not discuss the

special benefits and decisions for people who already have breast cancer.

Why do women and men use tamoxifen?

Tamoxifen has more than one use. Tamoxifen is used:

1. to lower the chance of getting breast cancer in women with a higher than normal chance of getting

breast cancer in the next 5 years (high-risk women).

2. to lower the chance of getting invasive (spreading) breast cancer in women who had surgery and

radiation for ductal carcinoma in situ (DCIS). DCIS means the cancer is only inside the milk ducts.

3. to treat breast cancer in women after they have finished early treatment. Early treatment can include

surgery, radiation, and chemotherapy. Tamoxifen may keep the cancer from spreading to other parts

of the body. It may also reduce the woman’s chance of getting a new breast cancer.

4. in women and men, to treat breast cancer that has spread to other parts of the body (metastatic breast

cancer).

This guide talks only about using tamoxifen to lower the chance of getting breast cancer (#1 and #2

above).

What are the benefits of tamoxifen to lower the chance of getting breast cancer in high-risk

women and in women treated for DCIS?

A large U.S. study looked at high-risk women and compared the ones who took tamoxifen for 5 years

with others who took a pill without tamoxifen (placebo). High-risk women were defined as women who

have a 1.7% or greater chance of getting breast cancer in the next 5 years, based on a special computer

program. In this study:

Out of every 1000 high-risk women who took a placebo, each year about 7 got breast cancer.

Out of every 1000 high-risk women who took tamoxifen, each year about 4 got breast cancer.

The study showed that on average, high-risk women who took tamoxifen lowered their chances of

getting breast cancer by 44%, from 7 in 1000 to 4 in 1000.

Another U.S. study looked at women with DCIS and compared those who took tamoxifen for 5 years

with others who took a placebo. In this study:

Out of every 1000 women with DCIS who took placebo, each year about 17 got breast cancer.

Out of every 1000 women with DCIS who took tamoxifen, each year about 10 got breast cancer.

The study showed that on average, women with DCIS who took tamoxifen lowered their chances of

getting invasive (spreading) breast cancer by 43%, from 17 in 1000 to 10 in 1000.

These studies do not mean that taking tamoxifen will lower your personal chance of getting

breast cancer. We do not know what the benefits will be for any one woman who takes tamoxifen

citrate to reduce her chance of getting breast cancer.

What are the risks of tamoxifen?

In the studies described under “ What are the benefits of tamoxifen?”, the high-risk women who took

tamoxifen citrate got certain side effects at a higher rate than those who took a placebo. Some of these

side effects can cause death.

In one study, in women who still had their uterus:

Out of every 1000 women who took a placebo, each year 1 got endometrial cancer (cancer of the

lining of the uterus) and none got uterine sarcoma (cancer of the body of the uterus).

Out of every 1000 women who took tamoxifen, each year 2 got endometrial cancer and fewer than 1

got uterine sarcoma.

These results show that, on average, in high-risk women who still had their uterus, tamoxifen citrate

doubled the chance of getting endometrial cancer from 1 in 1000 to 2 in 1000, and it increased the

chance of getting uterine sarcoma. This does not mean that taking tamoxifen will double your

personal chance of getting endometrial cancer or increase your chance of getting uterine

sarcoma. We do not know what this risk will be for any one woman. The risk is different for women

who no longer have their uterus.

For all women in this study, taking tamoxifen increased the risk of having a blood clot in their

lungs or veins, or of having a stroke. In some cases, women died from these effects.

Tamoxifen increased the risk of getting cataracts (clouding of the lens of the eye) or needing

cataract surgery. (See “ What are the possible side effects of tamoxifen?” for more details about

side effects.)

What don’t we know about taking tamoxifen citrate to reduce the chance of getting breast

cancer?

We don’t know:

if tamoxifen lowers the chance of getting breast cancer in women who have abnormal breast cancer

genes (BRCA1 and BRCA2)

if taking tamoxifen for 5 years reduces the number of breast cancers a woman will get in her lifetime

or if it only delays some breast cancers

if tamoxifen helps a woman live longer

the effects of taking tamoxifen with hormone replacement therapy (HRT), birth control pills, or

androgens (male hormones)

the benefits of taking tamoxifen if you are less than 35 years old

Studies are being done to learn more about the long-term benefits and risks of using tamoxifen to reduce

the chance of getting breast cancer.

What are the possible side effects of tamoxifen?

The most common side effect of tamoxifen is hot flashes. This is not a sign of a serious problem.

The next most common side effect is vaginal discharge. If the discharge is bloody, it could be a sign of

a serious problem. [See “ Changes in the lining (endometrium) or body of your uterus” below.]

Less common but serious side effects of tamoxifen are listed below. These can occur at any time. Call

your doctor right away if you have any signs of side effects listed below:

Changes in the lining (endometrium) or body of your uterus. These changes may mean serious

problems are starting, including cancer of the uterus. The signs of changes in the uterus are:

- Vaginal bleeding or bloody discharge that could be a rusty or brown color. You should call your

doctor even if only a small amount of bleeding occurs.

- Change in your monthly bleeding, such as in the amount or timing of bleeding or increased clotting.

- Pain or pressure in your pelvis (below your belly button).

Blood clots in your veins or lungs. These can cause serious problems, including death. You may

get clots up to 2 to 3 months after you stop taking tamoxifen citrate. The signs of blood clots are:

- sudden chest pain, shortness of breath, coughing up blood

- pain, tenderness, or swelling in one or both of your legs

Stroke. Stroke can cause serious medical problems, including death. The signs of stroke are:

- sudden weakness, tingling, or numbness in your face, arm or leg, especially on one side of your body

- sudden confusion, trouble speaking or understanding

- sudden trouble seeing in one or both eyes

- sudden trouble walking, dizziness, loss of balance or coordination

- sudden severe headache with no known cause

Cataracts or increased chance of needing cataract surgery. The sign of these problems is slow

blurring of your vision.

Liver problems, including jaundice. The signs of liver problems include lack of appetite and

yellowing of your skin or whites of your eyes.

These are not all the possible side effects of tamoxifen. For a complete list, ask your doctor or

pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

Who should not take tamoxifen?

Do not take tamoxifen for any reason if you

Are pregnant or plan to become pregnant while taking tamoxifen or during the 2 months after

you stop taking tamoxifen. Tamoxifen may harm your unborn baby. It takes about 2 months to

clear tamoxifen from your body. To be sure you are not pregnant, you can start taking tamoxifen

while you are having your menstrual period. Or, you can take a pregnancy test to be sure you are not

pregnant before you begin.

Are breast feeding. We do not know if tamoxifen can pass through your milk and harm your baby.

Have had an allergic reaction to tamoxifen or to any of its inactive ingredients.

If you get pregnant while taking tamoxifen, stop taking it right away and contact your doctor.

Tamoxifen may harm your unborn baby.

Do not take tamoxifen to lower your chance of getting breast cancer if:

You ever had a blood clot that needed medical treatment.

You are taking medicines to thin your blood, like warfarin, (also called Coumadin®*).

Your ability to move around is limited for most of your waking hours.

You are at risk for blood clots. Your doctor can tell you if you are at high risk for blood clots.

You do not have a higher than normal chance of getting breast cancer. Your doctor can tell you if

you are a high-risk woman.

How should I take tamoxifen?

Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take tamoxifen

with or without food. Take your medicine every day. It may be easier to remember if you take it at

the same time each day.

If you forget a dose, take it when you remember, then take the next dose as usual. If it is almost time

for your next dose or you remember at your next dose, do not take extra tablets to make up the

missed dose.

Take tamoxifen for 5 years, unless your doctor tells you otherwise.

What should I avoid while taking tamoxifen?

Do not become pregnant while taking tamoxifen or for 2 months after you stop. Tamoxifen can

stop hormonal birth control methods from working. Hormonal methods include birth control pills,

patches, injections, rings and implants. Therefore, while taking tamoxifen, use birth control

methods that don’t use hormones, such as condoms, diaphragms with spermicide, or plain IUD’s.

If you get pregnant, stop taking tamoxifen right away and call your doctor.

Do not breastfeed. We do not know if tamoxifen can pass through your milk and if it can harm the

baby.

What should I do while taking tamoxifen?

Have regular gynecology check-ups (“female exams”), breast exams and mammograms. Your doctor

will tell you how often. These will check for signs of breast cancer and cancer of the endometrium

(lining of the uterus). Because tamoxifen does not prevent all breast cancers, and you may get other

types of cancers, you need these exams to find any cancers as early as possible.

Because tamoxifen can cause serious side effects, pay close attention to your body. Signs you

should look for are listed in “ What are the possible side effects of tamoxifen?

Tell all of the doctors that you see that you are taking tamoxifen.

Tell your doctor right away if you have any new breast lumps.

General information about the safe and effective use of tamoxifen.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Your

doctor has prescribed tamoxifen only for you. Do not give it to other people, even if they have a similar

condition, because it may harm them. Do not use it for a condition for which it was not prescribed.

This Medication Guide is a summary of information about tamoxifen for women who use tamoxifen to

lower their high chance of getting breast cancer or who have DCIS. If you want more information about

tamoxifen, ask your doctor or pharmacist. They can give you information about tamoxifen that is written

for health professionals. For more information about tamoxifen or breast cancer, call 1-800-272-5525.

Ingredients: tamoxifen citrate, croscarmellose sodium, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, and pregelatinized starch.

*Coumadin® is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: April 2015

PRINCIPAL DISPLAY PANEL

TAMOXIFEN CITRATE

tamoxifen citrate tablet

Product Information

NuCare Pharmaceuticals,Inc.

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-50 0 5(NDC:0 59 1-2473)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TAMO XIFEN CITRATE (UNII: 7FRV7310 N6 ) (TAMOXIFEN - UNII:0 9 4ZI8 1Y45)

TAMOXIFEN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

Product Characteristics

Color

white

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

10 mm

Flavor

Imprint Code

2233;WPI

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-50 0 5-3

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/29 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 70 9 29

0 8 /15/20 11

Labeler -

NuCare Pharmaceuticals,Inc. (010632300)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals,Inc.

0 10 6 3230 0

re la be l(6 8 0 71-50 0 5)

Revised: 7/2019

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