TAMOXIFEN CITRATE TABLETS, USP

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 1,000 women-years of 2.20 for tamoxifen vs. 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for tamoxifen vs. 0.04 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for tamoxifen vs. 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 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 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. SeeWARNINGS: Effects on the Uterus - Endometrial Cancer and Uterine Sarcoma.

**See Table 3 underCLINICAL PHARMACOLOGY - Clinical Studies.

Tamoxifen citrate tablets USP, a nonsteroidal antiestrogen, are for oral administration. Tamoxifen citrate tablets are available as:

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: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

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 and molecular formulas are:

Tamoxifen citrate has a molecular weight of 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.

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.

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether five 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: 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 ≥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 5 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 (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.

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<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (≤49, 50-59, ≥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: 0.39-1.11).

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: 0.73-1.49).

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). No information regarding bone mineral density or other markers of osteoporosis is available.

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: 1.27-4.92). Deep vein thrombosis was observed in 30 women receiving tamoxifen vs. 19 in women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the tamoxifen group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the tamoxifen arm and 24 on the placebo arm (RR=1.42; 95% CI: 0.82-2.51). 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: 1.00-1.28). 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 1.21-1.89) (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 1,000 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 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.

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, 5,408 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.

• 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 1 breast biopsy; or
• LCIS

• 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.

• At least 2 first degree relatives with 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.

• At least 2 first degree relatives with a history of breast cancer; or
• History of one 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 two breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more.

• 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.

• 5-year predicted risk of breast cancer ≥ 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 1-866-292-6719.

There are no data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2).

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 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).

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.

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.

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.

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.

Signs observed at the highest doses following studies to determine LD₅₀ 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 3-5 days of beginning tamoxifen and cleared within 2-5 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/m² loading dose, followed by maintenance doses of 150 mg/m² 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/m² loading dose, followed by maintenance doses of 80 mg/m² of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m² 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.

For patients with breast cancer, the recommended daily dose is 20-40 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 five 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 five years of adjuvant tamoxifen therapy for patients with breast cancer.

10 mg Tablets: Tamoxifen Citrate Tablets, USP are available as 10 mg tablets (containing 15.2 mg tamoxifen citrate in an amount equivalent to 10 mg of tamoxifen) round, biconvex, uncoated, white tablet unscored identified with "964" debossed on one side and the debossed on the other side are supplied in bottles of 60 tablets (NDC 62037-964-60), 180 tablets (NDC 62037-964-18) and 2500 tablets (NDC 62037-964-25).

20 mg Tablets: Tamoxifen Citrate Tablets, USP are available as 20 mg tablets (containing 30.4 mg tamoxifen citrate in an amount equivalent to 20 mg of tamoxifen) round, biconvex, uncoated, white tablet unscored identified with "965" debossed on one side and the debossed on the other side are supplied in bottles of 30 tablets (NDC 62037-965-30), 90 tablets (NDC 62037-965-90) and 1250 tablets (NDC 62037-965-12).

Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed, light-resistant container.

Manufactured by:
Andrx Pharmaceuticals, Inc.
Ft. Lauderdale, FL 33314
Toll Free 1-866-292-6719

Rev. date: 02/03A
7227

TAMOXIFEN CITRATE TABLETS

for Breast Cancer Treatment and Reduction in the Incidence of Breast Cancer

Generic Name: Tamoxifen (ta-MOX-i-fen)

Please read this information carefully before you begin taking tamoxifen. It is important to read this information each time your prescription is filled or refilled in case new information is available. This summary does not tell you everything about tamoxifen. Your health care professional is the best source of information about this medicine. You should talk with him or her before you begin taking tamoxifen and at regular check-ups. In addition, the professional package insert contains more detailed information on tamoxifen.

What are the most important things I should know about tamoxifen citrate tablets?

Tamoxifen has been shown to help women with advanced breast cancer and in clinical trials of over 30,000 women with early breast cancer it has been shown to reduce the risk of recurrence. Also in a trial of 13,000 women at high risk of breast cancer, tamoxifen reduced the risk of developing the disease.

Like all medicines, tamoxifen has some side effects. Most are mild and relate to its hormonal mode of action. For all women tamoxifen can, however, also increase the risk of some serious and potentially life-threatening events, including, uterine cancer, blood clots, and stroke. Some of these events have caused death. Tamoxifen can also increase the risk of getting cataracts or of needing cataract surgery. If you experience symptoms of any of these, tell you doctor immediately (see "What should I avoid or do while taking tamoxifen?").

If you are a woman at high risk for breast cancer or a woman with DCIS considering tamoxifen to reduce your risk of developing breast cancer, you should discuss the potential benefits versus the potential risks of these serious events with your health care provider.

What is tamoxifen?

• tamoxifen is a prescription medicine used to reduce the risk of getting breast cancer (in women who have a high risk of getting breast cancer).
  This effect was shown in the Breast Cancer Prevention Trial (BCPT, NSABP P-1), a large study where over 13,000 women at high risk for breast cancer were to take tamoxifen or placebo (a pill without tamoxifen) for 5 years. High risk women were those who were at least 35 years old and had a combination of risks that made their chances of developing breast cancer greater than 1.67% in the next 5 years. The risk factors included early age at first menstrual period, late age at first pregnancy, no pregnancies, close family members with breast cancer (mother, sister, or daughter), history of previous breast biopsies, or high-risk changes in the breast seen on a biopsy. Twenty-five percent of the women in the study completed 5 years of treatment, and most women in this study have been followed for about 4 years. The study showed that tamoxifen reduced the chance of getting breast cancer by 44%. The longer-term effects of tamoxifen on reducing the chance of getting breast cancer are not known.

We do not know whether taking tamoxifen for 5 years only delays the appearance of cancer, or actually decreases the number of tumors that will ever develop since long-term studies have not been completed.

Some women in this study also experienced serious side effects of tamoxifen. They are described in detail in the section, What are the possible side effects of tamoxifen?. Some of these women experienced complications related to the treatment of these side effects. The following table of the major results from the study is intended to be an aid in weighing the potential benefit of a reduction in risk of breast cancer against the potential risk of serious side effects of tamoxifen.

Two European trials of tamoxifen in women with a high risk of breast cancer were also conducted. They showed no difference in the number of breast cancer cases between the women who took tamoxifen and those who got placebo. These studies had trial designs that differed from that of NSABP P-1, were smaller than P-1, and enrolled women at a lower risk for breast cancer than those in the P-1 trial.

• In women with DCIS, following breast surgery and radiation, tamoxifen is indicated to reduce the risk of invasive 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 therapy.

A trial evaluated the addition of tamoxifen to lumpectomy and radiation therapy in women with DCIS. The primary objective was to determine whether 5 years of tamoxifen therapy would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. The incidence of invasive breast cancer was reduced by 43% among women treated with tamoxifen.

• Tamoxifen is used to reduce the recurrence of breast cancer in women who have had surgery and/or radiation therapy to treat early breast cancer. Tamoxifen is also used in women with breast cancer who are at risk of developing a second breast cancer in the opposite breast.

The Early Breast Cancer Triauls Collaborative Group reviewed the 10-year results of studies of tamoxifen for early breast cancer. Treatment with tamoxifen for about 5 years reduced the risk of recurrence of breast cancer and improved overall survival. Treatment with about 5 years of tamoxifen also reduced the chance of getting a second breast cancer in the opposite breast by approximately 50%, a result similar to that seen in the NSABP P-1 study.

• Tamoxifen is used to treat advanced breast cancer in women and men.

Three studies compared tamoxifen to surgery or radiation to the ovaries in premenopausal women with advanced breast cancer and found that tamoxifen was similar to surgery or radiation in causing tumor shrinkage.

Published studies have demonstrated that tamoxifen is effective for the treatment of advanced breast cancer in men.

• Tamoxifen is a prescription tablet available in two dosage strengths: 10 mg tablets and 20 mg tablets. The active ingredient in each tablet is tamoxifen citrate.

How does tamoxifen work?

Tamoxifen belongs to a group of medicines called antiestrogens. Antiestrogens work by blocking the effects of the hormone estrogen in the body. Estrogen may cause the growth of some types of breast tumors. Tamoxifen may block the growth of tumors that respond to estrogen.

Who should not take tamoxifen citrate tablets?

• You should not take tamoxifen to reduce the risk of getting breast cancer if you have ever had blood clots or if you develop blood clots that require medical treatment. However, if you are taking tamoxifen for treatment of early or advanced breast cancer, the benefits of tamoxifen may outweigh the risks associated with developing new blood clots. Your health care professional can assist you in deciding whether tamoxifen is right for you.
• You should not take tamoxifen to reduce the risk of getting breast cancer if you are taking medicines to thin your blood (anticoagulants) like warfarin (Coumadin^®*).
• You should not take tamoxifen if you plan to become pregnant while taking tamoxifen or during the two months after you stop taking it because tamoxifen may harm your unborn child. You should see your doctor immediately and stop taking tamoxifen if you become pregnant while taking the drug. Please talk with your doctor about birth control recommendations. If you are capable of becoming pregnant, you should start tamoxifen during a menstrual period or if you have irregular periods have a negative pregnancy test before beginning to take tamoxifen. Tamoxifen does not prevent pregnancy, even in the presence of menstrual irregularity.
• You should not take tamoxifen if you are breast feeding.
• You should not take tamoxifen if you have ever had an allergic reaction to tamoxifen or tamoxifen citrate (the chemical name) or any of its ingredients.
• Tamoxifen is not known to reduce the risk of breast cancer in women with changes in breast cancer genes (BRCA1 or BRCA2).
• You should not take tamoxifen to decrease the chance of getting breast cancer if you are less than age 35 because tamoxifen has not been tested in younger women.
• You should not take tamoxifen to reduce the risk of breast cancer unless you are at high risk of getting breast cancer. Certain conditions put women at high risk and it is possible to calculate this risk for any woman. Breast cancer risk assessment tools to help calculate your risk of breast cancer have been developed and are available to your health care professional. You should discuss your risks with your health care professional.

Girls with McCune-Albright Syndrome (a genetic condition associated with premature puberty) under the age of two and older than 10 years of age should not take tamoxifen because treatment in this age group has not been studied. Tamoxifen has not been studied in boys.

How should I take tamoxifen?

• Follow your doctor's instructions about when and how to take tamoxifen. Read the label on the container. If you are unsure or have questions, ask your doctor or pharmacist.
• You will take tamoxifen differently, depending on your diagnosis.
• For reduction of the risk of breast cancer, the usual dose is 20 mg a day, for five years.
• For treatment of breast cancer in adult women and men, the usual dose is 20-40 mg a day. Take the tablets once or twice a day depending on the tablet strength prescribed. If your doctor has prescribed a different dose, do not change it unless he or she tells you to do so. For women with early breast cancer, tamoxifen should be taken for 5 years. For women with advanced cancer, tamoxifen should be taken until your doctor feels it is no longer indicated.
• Take your medicine each day. You may find it easier to remember to take your medicine if you take it at the same time each day. If you forget to take a dose, take it as soon as you remember and then take the next dose as usual.
• Swallow the tablets whole with a drink of water.
• You can take tamoxifen with or without food.
• Do not stop taking your tablets unless your doctor tells you to do so.

Are there other important factors to consider before taking tamoxifen?

• Tell your doctor if you have ever had blood clots that required medical treatment.
• Because tamoxifen may affect how other medicines work, always tell your doctor if you are taking any other prescription or non-prescription (over-the-counter) medications, particularly if you are taking warfarin to thin your blood.
• You should not become pregnant when taking tamoxifen or during the two months after you stop taking it as tamoxifen may harm your unborn child. Please contact your doctor for birth control recommendations. Tamoxifen does not prevent pregnancy, even in the presence of menstrual irregularity. You should see your doctor immediately if you think you may have become pregnant after starting to take tamoxifen.

What should I avoid or do while taking tamoxifen?

• You should contact your doctor immediately if you notice any of the following symptoms. Some of these symptoms may suggest that you are experiencing a rare but serious side effect associated with tamoxifen (see "What are the possible side effects of tamoxifen?").
  • –new breast lumps
  • –vaginal bleeding
  • –changes in your menstrual cycle
  • –changes in vaginal discharge
  • –pelvic pain or pressure
  • –swelling or tenderness in your calf
  • –unexplained breathlessness (shortness of breath)
  • –sudden chest pain
  • –coughing up blood
  • –changes in your vision
  If you see a health care professional who is new to you (an emergency room doctor, another doctor in the practice), tell him or her that you take tamoxifen or have previously taken tamoxifen.

• Because tamoxifen may affect how other medicines work, always tell your doctor if you are taking any other prescription or non-prescription (over-the-counter) medicines. Be sure to tell your doctor if you are taking warfarin (Coumadin) to thin your blood.
• You should not become pregnant when taking tamoxifen or during the two months after you stop taking it because tamoxifen may harm your unborn child. You should see your doctor immediately if you think you may have become pregnant after starting to take tamoxifen. Please talk with your doctor about birth control recommendations. If you are taking tamoxifen to reduce your risk of getting breast cancer, and you are sexually active, tamoxifen should be started during your menstrual period. If you have irregular periods, you should have a negative pregnancy test before you start tamoxifen. Tamoxifen does not prevent pregnancy, even in the presence of menstrual irregularity.
• If you are taking tamoxifen to reduce your risk of getting breast cancer, you should know that tamoxifen does not prevent all breast cancers. While you are taking tamoxifen and after you stop taking tamoxifen and in keeping with your doctor's recommendation, you should have annual gynecological check-ups which should include breast exams and mammograms. If breast cancer occurs, there is no guarantee that it will be detected at an early stage. This is why it is important to continue with regular check-ups.

What are the possible side effects of tamoxifen?

Like many medicines, tamoxifen causes side effects in most patients. The majority of the side effects seen with tamoxifen have been mild and do not usually cause breast cancer patients to stop taking the medication. In women with breast cancer, withdrawal from tamoxifen therapy is about 5%. Approximately 15% of women who took tamoxifen to reduce the chance of getting breast cancer stopped treatment because of side effects.

The most common side effects reported with tamoxifen are: hot flashes; vaginal discharge or bleeding; and menstrual irregularities (these side effects may be mild or may be a sign of a more serious side effect). Women may experience hair loss, skin rashes (itching or peeling skin) or headaches; or inflammation of the lungs, which may have the same symptoms as pneumonia, such as breathlessness and cough; however, hair loss is uncommon and is usually mild.

A rare but serious side effect of tamoxifen is a blood clot in the veins. Blood clots stop the flow of blood and can cause serious medical problems, disability, or death. Women who take tamoxifen are at increased risk for developing blood clots in the lungs and legs. Some women may develop more than one blood clot, even if tamoxifen is stopped. Women may also have complications from treating the clot, such as bleeding from thinning the blood too much. Symptoms of a blood clot in the lungs may include sudden chest pain, shortness of breath or coughing up blood. Symptoms of a blood clot in the legs are pain or swelling in the calves. A blood clot in the legs may move to the lungs. If you experience any of these symptoms of a blood clot, contact your doctor immediately.

Tamoxifen increases the chance of having a stroke, which can cause serious medical problems, disability, or death. If you experience any symptoms of stroke, such as weakness, difficulty walking or talking, or numbness, contact your doctor immediately.

Tamoxifen increases the chance of changes occurring in the lining (endometrium) or body of your uterus, which can be serious and could include cancer. If you have not had a hysterectomy (removal of the uterus), it is important for you to contact your doctor immediately if you experience any unusual vaginal discharge, vaginal bleeding, or menstrual irregularities; or pain or pressure in the pelvis (lower stomach). These may be caused by changes to the lining (endometrium) or body of your uterus. It is important to bring them to your doctor's attention without delay as they can occasionally indicate the start of something more serious and even life-threatening.

Tamoxifen may cause cataracts or changes to parts of the eye known as the cornea or retina. Tamoxifen can increase the chance of needing cataract surgery, and can cause blood clots in the veins of the eye. Tamoxifen can result in difficulty in distinguishing different colors. If you experience any changes in your vision, tell your doctor immediately.

Rare side effects, which may be serious, include certain liver problems such as jaundice (which may be seen as yellowing of the whites of the eyes) or hypertriglyceridemia (increased levels of fats in the blood) sometimes with pancreatitis (pain or tenderness in the upper abdomen). Stop taking tamoxifen and contact your doctor immediately if you develop angioedema (swelling of the face, lips, tongue and/or throat) even if you have been taking tamoxifen for a long time.

If you are a woman receiving tamoxifen for treatment of advanced breast cancer, and you experience excessive nausea, vomiting or thirst, tell your doctor immediately. This may mean that there are changes in the amount of calcium in your blood (hypercalcemia). Your doctor will evaluate this.

In patients with breast cancer, a temporary increase in the size of the tumor may occur and sometimes results in muscle aches/bone pain and skin redness. This condition may occur shortly after starting tamoxifen and may be associated with a good response to treatment.

Many of these side effects happen only rarely. However, you should contact your doctor if you think you have any of these or any other problems with your tamoxifen. Some side effects of tamoxifen may become apparent soon after starting the drug, but others may first appear at any time during therapy.

This summary does not include all possible side effects with tamoxifen. It is important to talk to your health care professional about possible side effects. If you want to read more, ask your doctor or pharmacist to give you the professional labeling.

How should I store tamoxifen?

Tamoxifen citrate tablets should be stored at room temperature (68-77°F). Keep in a well-closed, light-resistant container. Keep out of the reach of children.

Do not take your tablets after the expiration date on the container. Be sure that any discarded tablets are out of the reach of children.

This leaflet provides you with a summary of information about tamoxifen. Medicines are sometimes prescribed for uses other than those uled. Tamoxifen has been prescribed specifically for you by your doctor. Do not give your medicine to anyone else, even if they have a similar condition, because it may harm them.

If you have any questions or concerns, contact your doctor or pharmacist. Your pharmacist also has a longer leaflet about tamoxifen written for health care professionals that you can ask to read. For more information about tamoxifen or breast cancer, call 1-866-292-6719.

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

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