Nolvadex

Tamoxifen is an anti-estrogen that prevents the effects of estrogens on tissues.

Take tamoxifen exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medication with a full glass (8 ounces) of water. Tamoxifen can be taken with or without food.

If you are taking tamoxifen to reduce your risk of breast cancer, you may need to take your first dose while you are having a menstrual period. You may also need to have a pregnancy test before you start taking tamoxifen, to make sure you are not pregnant. Follow your doctor's instructions.

Use tamoxifen regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely. You may need to keep using this medication for up to 5 years.

To make sure this medication is not causing harmful effects, your doctor may want you to have mammograms and to perform routine breast self-exams on a regular basis. Your liver function may also need to be tested. Visit your doctor regularly.

Store at room temperature away from moisture, heat, or cold. Do not freeze.

Tamoxifen Overdose

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Missed Dose of Tamoxifen

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double up to catch up.

NOLVADEX® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. NOLVADEX (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.

Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, NOLVADEX (tamoxifen citrate) 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 empirical 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.

MEDICATION GUIDE

NOLVADEX (tamoxifen citrate) ®
(NOLE-vah-dex) Tablets
Generic name: tamoxifen
(ta-MOX-I-fen)

Written for women who use NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) to lower the chance of getting breast cancer in high-risk women and in women treated for DCIS.

People taking NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) to lower your chance of getting breast cancer.

You and your doctor should talk about whether the possible benefit of NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) to decrease your chance of getting invasive (spreading) breast cancer.

Read this guide carefully before you start NOLVADEX (tamoxifen citrate) . 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 NOLVADEX (tamoxifen citrate) and does not take the place of talking with your doctor.

Only you and your doctor can determine if NOLVADEX (tamoxifen citrate) is right for you.

What is the most important information I should know about using NOLVADEX (tamoxifen citrate) to reduce the chance of getting breast cancer?

NOLVADEX (tamoxifen citrate) is a prescription medicine that is like estrogen (female hormone) in some ways and different in other ways. In the breast, NOLVADEX (tamoxifen citrate) can block estrogen's effects. Because it does this, NOLVADEX (tamoxifen citrate) may block the growth of breast cancers that need estrogen to grow (cancers that are estrogen- or progesterone-receptor positive).

NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) in lowering the chance of getting breast cancer is greater than its possible risks.

This Medication Guide reviews the risks and benefits of using NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) ?

NOLVADEX (tamoxifen citrate) has more than one use. NOLVADEX (tamoxifen citrate) 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. NOLVADEX (tamoxifen citrate) may keep the cancer from spreading to others 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 NOLVADEX (tamoxifen citrate) to lower the chance of getting breast cancer (#1 and #2 above).

What are the benefits of NOLVADEX (tamoxifen citrate) to lower the chance of getting breast cancer in high-risk women and in women treated for DCIS?

A large US study looked at high-risk women and compared the ones who took NOLVADEX (tamoxifen citrate) for 5 years with others who took a pill without NOLVADEX (tamoxifen citrate) (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 1,000 high-risk women who took a placebo, each year about 7 got breast cancer.
• Out of every 1,000 high-risk women who took NOLVADEX (tamoxifen citrate) , each year about 4 got breast cancer.

The study showed that on average, high-risk women who took NOLVADEX (tamoxifen citrate) lowered their chances of getting breast cancer by 44%, from 7 in 1,000 to 4 in 1,000.

Another US study looked at women with DCIS and compared those who took NOLVADEX (tamoxifen citrate) for 5 years with others who took a placebo. In this study:

• Out of every 1,000 women with DCIS who took placebo, each year about 17 got breast cancer.
• Out of every 1,000 women with DCIS who took NOLVADEX (tamoxifen citrate) , each year about 10 got breast cancer.

The study showed that on average, women with DCIS who took NOLVADEX (tamoxifen citrate) lowered their chances of getting invasive (spreading) breast cancer by 43%, from 17 in 1,000 to 10 in 1,000.

These studies do not mean that taking NOLVADEX (tamoxifen citrate) will lower your personal chance of getting breast cancer. We do not know what the benefits will be for any one woman who takes NOLVADEX (tamoxifen citrate) to reduce her chance of getting breast cancer.

What are the risks of NOLVADEX (tamoxifen citrate) ?

In the studies described under “What are the benefits of NOLVADEX (tamoxifen citrate) ?”, the high-risk women who took NOLVADEX (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 1,000 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 1,000 women who took NOLVADEX (tamoxifen citrate) , 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, NOLVADEX (tamoxifen citrate) doubled the chance of getting endometrial cancer from 1 in 1,000 to 2 in 1,000, and it increased the chance of getting uterine sarcoma. This does not mean that taking NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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.

NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) ?” for more details about side effects.)

What don't we know about taking NOLVADEX (tamoxifen citrate) to reduce the chance of getting breast cancer?

We don't know

• if NOLVADEX (tamoxifen citrate) lowers the chance of getting breast cancer in women who have abnormal breast cancer genes (BRCA1 and BRCA2)
• if taking NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) helps a woman live longer
• the effects of taking NOLVADEX (tamoxifen citrate) with hormone replacement therapy (HRT), birth control pills, or androgens (male hormones)
• the benefits of taking NOLVADEX (tamoxifen citrate) if you are less than 35 years old

Studies are being done to learn more about the long-term benefits and risks of using NOLVADEX (tamoxifen citrate) to reduce the chance of getting breast cancer.

What are the possible side effects of NOLVADEX (tamoxifen citrate) ?

The most common side effect of NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 2-3 months after you stop taking NOLVADEX (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 NOLVADEX (tamoxifen citrate) . For a complete list, ask your doctor or pharmacist.

Who should not take NOLVADEX (tamoxifen citrate) ?

Do not take NOLVADEX (tamoxifen citrate) for any reason if you

• Are pregnant or plan to become pregnant while taking NOLVADEX (tamoxifen citrate) or during the 2 months after you stop taking NOLVADEX (tamoxifen citrate) . NOLVADEX (tamoxifen citrate) may harm your unborn baby. It takes about 2 months to clear NOLVADEX (tamoxifen citrate) from your body. To be sure you are not pregnant, you can start taking NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) can pass through your milk and harm your baby.
• Have had an allergic reaction to NOLVADEX (tamoxifen citrate) or tamoxifen (the other name for NOLVADEX (tamoxifen citrate) ), or to any of its inactive ingredients.

If you get pregnant while taking NOLVADEX (tamoxifen citrate) , stop taking it right away and contact your doctor. NOLVADEX (tamoxifen citrate) may harm your unborn baby. Do not take NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) ?

• Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) for 5 years, unless your doctor tells you otherwise.

What should I avoid while taking NOLVADEX (tamoxifen citrate) ?

• Do not become pregnant while taking NOLVADEX (tamoxifen citrate) or for 2 months after you stop. NOLVADEX (tamoxifen citrate) can stop hormonal birth control methods from working. Hormonal methods include birth control pills, patches, injections, rings and implants. Therefore, while taking NOLVADEX (tamoxifen citrate) , 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 NOLVADEX (tamoxifen citrate) right away and call your doctor.
• Do not breast feed. We do not know if NOLVADEX (tamoxifen citrate) can pass through your milk and if it can harm the baby.

What should I do while taking NOLVADEX (tamoxifen citrate) ?

• 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) ?”
• Tell all of the doctors that you see that you are taking NOLVADEX (tamoxifen citrate) .
• Tell your doctor right away if you have any new breast lumps.

General information about the safe and effective use of NOLVADEX (tamoxifen citrate)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Your doctor has prescribed NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) for women who use NOLVADEX (tamoxifen citrate) to lower their high chance of getting breast cancer or who have DCIS. If you want more information about NOLVADEX (tamoxifen citrate) , ask your doctor or pharmacist. They can give you information about NOLVADEX (tamoxifen citrate) that is written for health professionals. For more information about NOLVADEX (tamoxifen citrate) or breast cancer, please visit www.NOLVADEX (tamoxifen citrate) .com or call 1-800-236-9933.

Ingredients: tamoxifen citrate, carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

This Medication Guide has been approved by the US Food and Drug Administration

• The most common side effect of Nolvadex 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.

Less common but serious side effects of Nolvadex 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 2-3 months after you stop taking Nolvadex. 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.

Do not take Nolvadex for any reason if you:

• Are pregnant or plan to become pregnant while taking Nolvadex or during the 2 months after you stop taking Nolvadex. Nolvadex may harm your unborn baby. It takes about 2 months to clear Nolvadex from your body. To be sure you are not pregnant, you can start taking Nolvadex 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 breastfeeding. We do not know if Nolvadex can pass through your milk and harm your baby.
• Have had an allergic reaction to Nolvadex or to any of its inactive ingredients.
• If you get pregnant while taking Nolvadex, stop taking it right away and contact your doctor. Nolvadex may harm your unborn baby.

Do not take Nolvadex 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.

• Importance of receiving routine gynecologic care and of immediately informing clinician if any new breast lumps or abnormal gynecologic symptoms, including abnormal vaginal bleeding, change in vaginal discharge, menstrual irregularities, or pelvic pain/pressure occur.128 163 183

• Importance of informing clinician of any changes in vision.128 190 191 192 193 258 268

• Importance of immediately informing clinician of unexplained shortness of breath or leg swelling/tenderness.128

• Importance of periodic monitoring, including liver function test monitoring and blood counts.128

• Advise patients at high risk of breast cancer that tamoxifen may decrease the incidence of breast cancer, but may not eliminate the risk of the disease.128

• Importance of women informing clinicians immediately if they are or plan to become pregnant; importance of avoiding pregnancy during therapy;119 128 243 importance of using effective nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the drug.a Necessity of advising pregnant patients of the risk to the fetus.128

• Importance of reading the medication guide; the guide is for women using tamoxifen to lower their risk of breast cancer or with DCIS.128

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.128

• Importance of women informing clinicians if they are or plan to breast-feed.128

• Importance of informing patients of other important precautionary information.128 (See Cautions.)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of tamoxifen in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Fluconazole
• Ketoconazole
• Mesoridazine
• Nelfinavir
• Pimozide
• Piperaquine
• Posaconazole
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Warfarin
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone
• Acenocoumarol
• Amiodarone
• Anagrelide
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Buserelin
• Capecitabine
• Ceritinib
• Chlorpromazine
• Clarithromycin
• Clobazam
• Clozapine
• Cobicistat
• Conivaptan
• Crizotinib
• Cyclophosphamide
• Dabrafenib
• Darunavir
• Dasabuvir
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Deutetrabenazine
• Dicumarol
• Domperidone
• Donepezil
• Doxifluridine
• Efavirenz
• Escitalopram
• Fluorouracil
• Fluoxetine
• Fluphenazine
• Fluvoxamine
• Foscarnet
• Fosphenytoin
• Genistein
• Gonadorelin
• Goserelin
• Histrelin
• Hydroxychloroquine
• Hydroxyzine
• Idelalisib
• Ipriflavone
• Ivabradine
• Leuprolide
• Levofloxacin
• Methadone
• Methotrexate
• Metronidazole
• Mitomycin
• Moxifloxacin
• Nafarelin
• Netupitant
• Ondansetron
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Phenprocoumon
• Phenytoin
• Pimavanserin
• Pitolisant
• Quetiapine
• Red Clover
• Ribociclib
• Ritonavir
• Sertraline
• Sevoflurane
• Sotalol
• St John's Wort
• Sulpiride
• Tacrolimus
• Tegafur
• Triptorelin
• Vandetanib
• Vemurafenib
• Vinflunine
• Zuclopenthixol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aldesleukin
• Aminoglutethimide
• Anastrozole
• Bexarotene
• Letrozole
• Rifampin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

For all patients
• Blood problems or
• Cataracts or other eye problems—Tamoxifen may also cause these problems.

• High cholesterol levels in the blood—Tamoxifen can increase cholesterol levels.

When used for reducing the risk for developing breast cancer in high-risk women or in women with Ductal Carcinoma in Situ (DCIS)
• Blood clots (or history of) or
• Pulmonary embolism (or history of) or
• Stroke or
• Uterine (womb) cancer—May increase risk of serious side effects from tamoxifen.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

A woman should contact her doctor right away if she develops:

• Changes in vaginal discharge or
• Changes in vision or
• Coughing up blood or
• Leg swelling or tenderness or
• Menstrual irregularities or
• New breast lumps or
• Pelvic pain or pressure or
• Sudden chest pain or
• Unexplained shortness of breath or
• Vaginal bleeding

If you seek medical attention for any reason, be sure to tell your doctor that you take tamoxifen or have taken tamoxifen.

For women: Tamoxifen may make you more fertile. It is best to use some type of birth control while you are taking it. However, do not use oral contraceptives (“the Pill”) since they may change the effects of tamoxifen. Tell your doctor right away if you think you have become pregnant while taking this medicine.

• Store at room temperature.
• Protect from heat.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Metastatic Breast Cancer:

Nolvadex is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, Nolvadex 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 Nolvadex therapy.

Adjuvant Treatment of Breast Cancer:

Nolvadex is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some Nolvadex adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes.

Nolvadex is 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 Nolvadex therapy is likely to be beneficial.

Nolvadex reduces the occurrence of contralateral breast cancer in patients receiving adjuvant Nolvadex therapy for breast cancer.

Ductal Carcinoma in Situ (DCIS):

In women with DCIS, following breast surgery and radiation, Nolvadex is indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with Nolvadex for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of Nolvadex therapy.

Current data from clinical trials support five years of adjuvant Nolvadex therapy for patients with breast cancer.

Reduction in Breast Cancer Incidence in High Risk Women:

Nolvadex is 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).

Nolvadex is 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 ≥ 1.67%, as calculated by the Gail Model.

Examples of combinations of factors predicting a 5-year risk ≥ 1.67% are:

•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

•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 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.

•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 1-800-544-2007.

There are insufficient data available regarding the effect of Nolvadex on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of Nolvadex in these patients.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with Nolvadex for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of Nolvadex therapy. In the NSABP P-1 trial, Nolvadex 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).

General:

Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking Nolvadex for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to Nolvadex 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 Nolvadex; this can sometimes be severe.

In the NSABP P-1 trial, 6 women on Nolvadex and 2 on placebo experienced grade 3-4 drops in platelet counts (≤50,000/mm3).

Information for Patients:

Patients should be instructed to read the Medication Guide supplied as required by law when Nolvadex is dispensed. The complete text of the Medication Guide is reprinted at the end of this document.

Women with DCIS treated with lumpectomy and radiation therapy who are considering Nolvadex to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with Nolvadex decreased the incidence of invasive breast cancer, but has not been shown to affect survival (See Table 1 in CLINICAL PHARMACOLOGY).

Women who are at high risk for breast cancer can consider taking Nolvadex 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. Nolvadex 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 Nolvadex 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 3in CLINICAL PHARMACOLOGY). Women should understand that Nolvadex reduces the incidence of breast cancer, but may not eliminate risk. Nolvadex 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 Nolvadex 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 Nolvadex to reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking Nolvadex 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, Nolvadex 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.

Women taking or having previously taken Nolvadex 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 Nolvadex.

Women taking Nolvadex 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 Nolvadex as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking Nolvadex for the reduction in the incidence of breast cancer. Women taking Nolvadex 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 Nolvadex (9% versus 3.5%, respectively).

Drug Interactions:

When Nolvadex 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 Nolvadex.

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 Nolvadex with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (ie, 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, Nolvadex should not be administered with anastrozole (see CLINICAL PHARMACOLOGY – Drug-Drug Interactions section).

Drug/Laboratory Testing Interactions:

During postmarketing surveillance, T4 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 Nolvadex.

In the postmarketing experience with Nolvadex, 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 section).

Carcinogenesis:

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/m2 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/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months.

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two 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/m2 basis).

Mutagenesis:

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 32P 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/m2 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/m2 basis) when female rats were dosed from days 7-17 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/m2 basis). There were no teratogenic changes in either rats or rabbits.

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 Nolvadex is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Nolvadex, women taking Nolvadex should not breast feed.

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

It is not known if Nolvadex is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Nolvadex, women taking Nolvadex should not breast feed.

Pediatric Use:

The safety and efficacy of Nolvadex for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Nolvadex therapy for girls have not been established. In adults treated with Nolvadex, 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 Nolvadex 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 section).

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 Nolvadex 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.

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 Nolvadex 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 Nolvadex 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 Nolvadex therapy for patients with breast cancer.

Ductal Carcinoma in Situ (DCIS):

The recommended dose is Nolvadex 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women:

The recommended dose is Nolvadex 20 mg daily for 5 years. There are no data to support the use of Nolvadex other than for 5 years (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women).

Summary of Use during Lactation

Since tamoxifen can suppress postpartum lactation and its excretion into breastmilk is not known, it should be avoided in nursing mothers.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Tamoxifen was more effective than placebo in suppressing lactation and preventing engorgement and pain in two trials in postpartum mothers. Neither study stated what, if any, physical methods (e.g., breast binding) were used concurrently.[1][2] In one study of 80 women, tamoxifen 10 mg four times daily for 5 days was more effective than placebo in suppressing a rise in serum prolactin after use of a mechanical breast pump after 5 days of treatment, but not on day 3. All of the women in the study had breastfed a previous child.[2] The other study of 150 women used 2 regimens: tamoxifen 30 mg twice daily for 2 days followed by 10 mg twice daily for 2 days; and 10 mg twice daily for 14 days. More women in the tamoxifen groups had not previously breastfed an infant.[1]

In a case report, a woman with a history of breastfeeding 4 children (the last having been weaned 10 months earlier) began lactating after 1 week of a cancer chemotherapy regimen for breast cancer that included tamoxifen 20 mg/day. Milk production continued for several weeks until tamoxifen was discontinued after which it did not return during 12 more weeks of chemotherapy.[3]

References

1. Shaaban MM. Suppression of lactation by an antiestrogen, tamoxifen. Eur J Obstet Gynecol Reprod Biol. 1975;4(5):167-9. PMID: 1053489

2. Masala A, Delitala G, Lo Dico G et al. Inhibition of lactation and inhibition of prolactin release after mechanical breast stimulation in puerperal women given tamoxifen or placebo. Br J Obstet Gynaecol. 1978;85:134-7. PMID: 626722

3. Favis GR, Alavi JB, Glick JH. Lactation from tamoxifen in breast cancer. Ann Intern Med. 1979;90:993-4. Letter. PMID: 220899

Substance Name

Tamoxifen

CAS Registry Number

10540-29-1

Drug Class

Antineoplastic Agents

Estrogen Antagonists

LactMed Record Number

250

Last Revision Date

20150310

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.