What is tamoxifen

Tamoxifen is a nonsteroidal antiestrogen or selective estrogen receptor modulator (SERM), that is widely used in the treatment and prevention of breast cancer. Tamoxifen is used to treat breast cancer that has spread to other parts of the body in men and women. Tamoxifen blocks the activity of estrogen (a female hormone) in the breast. This may stop the growth of some breast tumors that need estrogen to grow. It should be noted that evidence suggests that patients with estrogen receptor positive tumors (breast cancer with cells that have estrogen and/or progesterone receptors on them) are more likely to benefit from tamoxifen ¹. Tamoxifen also has many off-labeled uses, and they may require additional data ².

Tamoxifen is used to treat early breast cancer in women who have already been treated with surgery, radiation, and/or chemotherapy. Tamoxifen is used to reduce the risk of developing a more serious type of breast cancer in women who have had ductal carcinoma in situ (DCIS; a type of breast cancer that does not spread outside of the milk duct where it forms) and who have been treated with surgery and radiation. Tamoxifen is also used to reduce the risk of breast cancer in women who are at high risk for the disease due to their age, personal medical history, and family medical history.

Tamoxifen may also have other, as yet undefined, anticancer effects. Tamoxifen was approved for use in the United States in 1977 and is still widely used, being considered a first line adjuvant therapy for breast cancer. Current indications include both treatment of breast cancer and reduction of breast cancer risk in women at high risk.

Tamoxifen is available in 10 and 20 mg tablets to take by mouth and under several trade names such as Nolvadex and Tamone. Tamoxifen is also available as an oral solution (10 mg/5 mL). The usual dose for treating breast cancer is 20 to 40 mg daily, and for secondary prevention is 20 mg once daily for five years. Tamoxifen is usually taken once or twice a day with or without food. Take tamoxifen at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain anything you do not understand. Take tamoxifen exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow tamoxifen tablets whole; do not split, chew, or crush them. Swallow the tablets with water or any other nonalcoholic drink.

To lower the risk of breast cancer, tamoxifen is taken for 5 years. If you are taking tamoxifen to treat breast cancer, your doctor will decide how long your treatment will last. Do not stop taking tamoxifen without talking to your doctor.

If you forget to take a dose of tamoxifen, take the missed dose as soon as you remember it, and take your next dose as usual. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Tamoxifen can be taken whether or not you have gone through menopause, but raloxifene is only approved for post-menopausal women.

Tamoxifen common side effects include hot flashes, nausea, diarrhea, weight change and fluid retention.

How much does tamoxifen lowers the risk of breast cancer?

The effect of tamoxifen on breast cancer risk has varied in different studies. When the results of all the studies are taken together, the overall reduction in risk for tamoxifen is about 40% (more than a third). Tamoxifen and raloxifene lower the risk of both invasive breast cancer and ductal carcinoma in situ (DCIS).

What would this mean for me?

Although a medicine that cuts your risk by about 40% sounds like it must be a good thing, what it would really mean for you depends on how high your risk is in the first place (your baseline risk).

For example, if you had an 8% risk of getting breast cancer in the next 5 years, you would be considered to be at increased risk. An 8% risk would mean that over the next 5 years, 8 of 100 women with your risk would be expected to get breast cancer. A 40% reduction in your risk would mean your risk goes down to 5%. This would be only a 3% change overall.

Since the change in your overall risk depends on your baseline risk, you would benefit less if you had a lower baseline risk, and you would benefit more if your risk was higher. If you had a baseline risk of only 1.7% in the next 5 years (which is what many organizations use as a cutoff point for being at ‘increased risk’), the 40% change would mean that your risk would go down to about 1% in the next 5 years. This means your overall risk in the next 5 years would go down by less than 1%.

Your doctor can estimate your breast cancer risk based on factors like your age, medical history, and family history. This can help you see how much benefit you might get from taking one of these drugs.

Are there other benefits to tamoxifen?

Both tamoxifen and raloxifene can help prevent osteoporosis, a severe weakening of the bones that is more common after menopause.

Monitoring

All patients on tamoxifen should have routine lab work including a complete blood count with platelets, serum calcium, and liver function tests. Female patients should monitor for abnormal vaginal bleeding and receive a breast and gynecologic exam at baseline and routinely after. Patients should also watch for signs and symptoms of a deep vein thrombosis (DVT) or pulmonary embolism (PE).

Other monitoring parameters tend to vary, depending on patient-specific factors. In patients with pre-existing hyperlipidemia, triglycerides and cholesterol should be monitored ³. Patients on vitamin K antagonists should have their INR and PT checked ⁴. Reproductive female patients need a pregnancy test before treatment and should use reliable birth control methods during treatment ⁵. Premenopausal women should receive a bone mineral density test. All patients should get an ophthalmic exam if vision problems or cataracts occur ⁶.

Tamoxifen mechanism of action

Tamoxifen is referred to as a selective estrogen receptor modulator (SERM) with tissue specific actions because it has estrogenic effects on bone, brain and liver, but antagonist activity on breast tissue. Because tamoxifen has two actions, tamoxifen is patient-specific. Estrogen can fuel the growth of breast cancer cells. Tamoxifen blocks estrogen in breast cells, which is why tamoxifen can be useful in lowering breast cancer risk. In the breast tissue, tamoxifen competes with estrogen for binding sites and causes antiestrogenic and antitumor effects. Through downstream intracellular processes, tamoxifent slows cell cycling which classifies it as cytostatic. In the bone tamoxifen stimulates estrogen receptors instead of blocking them, exerting an estrogenic agonist effect, and may prevent osteoporosis in postmenopausal women ⁷.

What is tamoxifen used for?

US Food and Drug Administration (FDA)-Approved Uses

• Treatment of breast cancer in both females and males ⁸
• Adjuvant treatment of breast cancer after patients have completed their primary treatment with surgery and radiation ⁹
• Treatment of female patients with ductal carcinoma in situ (non-invasive breast cancer) after surgery and radiation to reduce the risk of invasive breast cancer ¹⁰
• Breast cancer risk reduction in certain patients at high risk (5-year risk = 1.67% calculated by the Gail Model) ¹¹.

Non-FDA-Approved Uses

• Treatment of progressive or recurrent desmoid tumors in combination with sulindac ¹²
• Treatment of endometrioid histologies that are recurrent, metastatic, or at high-risk ¹³
• Treatment of primary or secondary gynecomastia along with breast pain associated with it ¹⁴
• Induction of ovulation in the treatment of infertility ¹⁵
• Treatment of oligospermia in combination with testosterone ¹⁶
• Prophylaxis of coronary arteriosclerosis in men with triple vessel ¹⁷
• Treatment of advanced or recurrent ovarian cancer ¹⁸
• Treatment of bladder cancer ¹⁹
• Treatment of lung cancer in addition to initial chemotherapy treatment ²⁰
• Treatment of precocious puberty due to McCune-Albright syndrome in females (a condition that may cause bone disease, early sexual development, and dark colored spots on the skin in children) ²¹
• Treatment of metastatic malignant melanoma in combination with other agents including carmustine, cisplatin, and dacarbazine ²²
• Treatment of benign mammary dysplasia ²³
• Treatment of bone metastasis ²⁴
• Treatment of carcinoid tumor ²⁵
• Treatment of cutaneous polyarteritis nodosa ²⁶
• Treatment of hypertrophy of uterus ²⁷
• Treatment of meningioma ²⁸
• Treatment of primary breast pain, premenstrual mastodynia, or breast pain that originated from liver cirrhosis ²⁹
• Prophylaxis of postmenopausal osteoporosis ³⁰
• Improvement of length and quality of life in patients with retinoblastoma in addition to treatment protocols ³¹
• Treatment of Riedel’s thyroiditis ³²
• Treatment of solid tumor secondary malignant neoplasms ³³

Tamoxifen contraindications

Tamoxifen should not be used in patients with a known allergy to it or any component in its formulation or concomitantly with warfarin. For patients taking tamoxifen for breast cancer risk reduction who are at high risk for breast cancer or with ductal carcinoma in situ, it should be avoided if the patient has a history of deep vein thrombosis (DVT) or pulmonary embolism (PE). In patients that have been diagnosed with breast cancer, the benefits outweigh the risks, but it should still be used in caution in patients with a history of thromboembolic events.

Tamoxifen also has many drug-drug interactions, so a comprehensive medication list in all patients receiving it is vital ³⁴.

Tamoxifen special precautions

Before taking tamoxifen:

• tell your doctor and pharmacist if you are allergic to tamoxifen or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: aminoglutethimide (Cytadren); anastrozole (Arimidex), bromocriptine (Parlodel); cancer chemotherapy medication such as cyclophosphamide (Cytoxan, Neosar) letrozole (Femara); medroxyprogesterone (Depo-Provera, Provera, in Prempro); phenobarbital; and rifampin (Rifadin, Rimactane). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  in addition to the conditions listed in the IMPORTANT WARNING section, tell your doctor if you have or have ever had high blood levels of cholesterol.
• tell your doctor if you are pregnant or plan to become pregnant. You should not plan to become pregnant while taking tamoxifen or for 2 months after your treatment. Your doctor may perform a pregnancy test or tell you to begin your treatment during your menstrual period to be sure that you are not pregnant when you begin taking tamoxifen. You will need to use a reliable nonhormonal method of birth control to prevent pregnancy while you are taking tamoxifen and for 2 months after your treatment. Talk to your doctor about the types of birth control that are right for you, and continue to use birth control even if you do not have regular menstrual periods during your treatment. Stop taking tamoxifen and call your doctor right away if you think you have become pregnant during your treatment. Tamoxifen may harm the fetus.
• tell your doctor if you are breast-feeding. You should not breastfeed during your treatment with tamoxifen.
• tell all of your doctors and other health care providers that you are taking tamoxifen.
• you will still need to look for early signs of breast cancer since it is possible to develop breast cancer even during treatment with tamoxifen. Talk to your doctor about how often you should examine your breasts yourself, have a doctor examine your breasts, and have mammograms (x-ray examinations of the breasts). Call your doctor right away if you find a new lump in your breast.

Other Medical Problems

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

• Blood clots (e.g., deep vein thrombosis, pulmonary embolism) or history of—Should not be used in patients with this condition.
• Eye or vision problems (eg, cataracts) or
• Hypercalcemia (high calcium levels in the blood) or
• Hyperlipidemia (high cholesterol levels in the blood) or
• Liver disease or
• Stroke, history of—Use with caution. May make these conditions worse.

Tamoxifen interactions

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 tamoxifen, 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 tamoxifen with any of the following medicines is not recommended. Your doctor may decide not to treat you with tamoxifen or change some of the other medicines you take.

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

Using tamoxifen 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 Acetate
• Amiodarone
• Anagrelide
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Buprenorphine
• Buserelin
• Capecitabine
• Carbamazepine
• Ceritinib
• Chloroquine
• Cinacalcet
• Clarithromycin
• Clobazam
• Clofazimine
• Clozapine
• Conivaptan
• Crizotinib
• Cyclophosphamide
• Dabrafenib
• Darunavir
• Dasatinib
• Degarelix
• Delamanid
• Deslorelin
• Deutetrabenazine
• Domperidone
• Donepezil
• Doxepin
• Doxifluridine
• Efavirenz
• Encorafenib
• Enzalutamide
• Escitalopram
• Fingolimod
• Fluorouracil
• Fluoxetine
• Fluvoxamine
• Foscarnet
• Fosnetupitant
• Fosphenytoin
• Genistein
• Glasdegib
• Gonadorelin
• Goserelin
• Histrelin
• Hydroxychloroquine
• Hydroxyzine
• Inotuzumab Ozogamicin
• Ipriflavone
• Ivabradine
• Ivosidenib
• Leuprolide
• Levofloxacin
• Lofexidine
• Lumacaftor
• Macimorelin
• Methadone
• Methotrexate
• Metronidazole
• Mitomycin
• Mitotane
• Moclobemide
• Moxifloxacin
• Nafarelin
• Netupitant
• Nilotinib
• Ondansetron
• Osimertinib
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Phenytoin
• Pimavanserin
• Pitolisant
• Quetiapine
• Quinine
• Red Clover
• Ribociclib
• Rifampin
• Rolapitant
• Sertraline
• Sevoflurane
• Siponimod
• Sotalol
• St John’s Wort
• Sulpiride
• Tacrolimus
• Tegafur
• Triclabendazole
• Triptorelin
• Vandetanib
• Vemurafenib
• Vinflunine
• Zuclopenthixol

Using tamoxifen 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

Other Interactions

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.

Tamoxifen dosage

Tamoxifen is available in a tablet (10 mg or 20 mg) or an oral solution (10 mg/5 mL). If it as administered as an oral solution, it is important to use the supplied dosing cup for adequate administration. The American Society of Clinical Oncology guidelines for Adjuvant Endocrine Therapy of Hormone-Receptor Positive Breast Cancer recommends a dose of 20 mg daily for breast cancer prevention after completion of chemotherapy. The duration of endocrine therapy depends on the patient’s menopausal status and can last 5 to 10 years ³⁵. For the treatment of metastatic breast cancer, 20 to 40 mg daily is recommended, although clinical benefit has not been shown for doses above 20 mg daily ³⁶. In some off-label clinical trials, 10 mg was used as the dose. It may be taken with or without food.

The amount of tamoxifen that you take depends on the strength of tamoxifen. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (solution, tablets):

• For breast cancer:
  • Adults—20 to 40 milligrams (mg) per day. Doses greater than 20 mg are given as 2 divided doses per day (morning and evening).
  • Children—Use and dose must be determined by your doctor.
• For breast cancer as additional treatment:
  • Adults—20 milligrams (mg) per day for 5 to 10 years.
  • Children—Use and dose must be determined by your doctor.
• For reducing the risk of developing breast cancer in high-risk women:
  • Adults—20 milligrams (mg) per day for 5 years.
  • Children—Use and dose must be determined by your doctor.
• For reducing the risk of developing invasive breast cancer in women with ductal carcinoma in situ (DCIS):
  • Adults—20 milligrams (mg) per day for 5 years.
  • Children—Use and dose must be determined by your doctor.

Adult dose for breast cancer

Uses:

• Metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, this drug is an alternative to oophorectomy or ovarian irradiation. Patients whose tumors are estrogen receptor positive are more likely to benefit.
• Ductal Carcinoma in Situ (DCIS): In women with DCIS, following breast surgery and radiation, to reduce the risk of invasive breast cancer.
• Reduction in Breast Cancer Incidence in High Risk Women: To reduce the incidence of breast cancer in women at high risk. “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.

Metastatic breast cancer in women and men:

• 20 to 40 mg orally daily for 5 years; doses greater than 20 mg should be given in divided doses (morning and evening)

Ductal Carcinoma in Situ (DCIS) following breast surgery and radiation:

• 20 mg orally daily for 5 years

To reduce the incidence of breast cancer in women at high risk for breast cancer:

• 20 mg orally daily for 5 years

Comments:

• There are no data to support the use of this drug other than for 5 years.

Adult dose for Breast Cancer – Adjuvant

Use: For the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation

• 20 mg orally once daily or 10 mg orally 2 times daily
• Duration of therapy: Up to 5 years

Comments:

• There are no data to support the use of this drug other than for 5 years.

Pediatric dose for McCune-Albright Syndrome

Use: McCune-Albright Syndrome; precocious puberty

Girls 2 to 10 years with McCune-Albright Syndrome and precocious puberty:

• 20 mg orally once daily
• Duration of therapy: Up to 12 months

Pediatric dose for Precocious Puberty

Use: McCune-Albright Syndrome; precocious puberty

Girls 2 to 10 years with McCune-Albright Syndrome and precocious puberty:

• 20 mg orally once daily
• Duration of therapy: Up to 12 months

Renal Dose Adjustments

• Data not available

Liver Dose Adjustments

• Data not available

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Tamoxifen adverse effects

Tamoxifen has a black box warning for uterine malignancies, pulmonary embolism, and stroke in patients who are at high risk for cancer or who have ductal carcinoma in situ (DCIS) ³⁷. In patients who are female, tamoxifen is associated with an increased incidence of uterine or endometrial cancers, with some being fatal. In patients who were already diagnosed with breast cancer, however, the benefits outweigh the risks ³⁸.

Like many cancer drugs, tamoxifen has many adverse effects associated with it, though serious and fatal ones are rare. The most common adverse effects seen in treatment are hot flashes, irregular periods, and vaginal discharge. Other common adverse effects include peripheral edema, hypertension, mood changes, pain, depression, skin changes and skin rashes, nausea and vomiting, weakness, arthritis, arthralgia, lymphedema, and pharyngitis.

Less common adverse effects may include insomnia, dizziness, headache, weight gain, abdominal pain, diarrhea, indigestion, urinary tract infections, thrombocytopenia, back pain, alopecia, ostealgia, and cataracts among many more. Due to the extensive adverse effects of tamoxifen, it is important for patients to discuss all adverse effects they are experiencing with their doctor ³⁹.

Tamoxifen can also cause a local disease flare which may lead to increased bone and tumor pain. This can be associated with good tumor response and usually resolves quickly. In patients with bone metastasis, hypercalcemia may occur. If hypercalcemia becomes severe and not manageable, discontinue tamoxifen ⁴⁰.

Tamoxifen side effects

Tamoxifen may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• increased bone or tumor pain
• pain or reddening around the tumor site
• hot flashes
• nausea
• excessive tiredness
• dizziness
• depression
• headache
• thinning of hair
• weight loss
• stomach cramps
• constipation
• loss of sexual desire or ability (in men)

More common side effects:

• absent, missed, or irregular menstrual periods
• bladder pain
• blindness
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• chills
• confusion
• cough
• decrease in the amount of urine
• decrease in height
• decreased vision
• difficult or labored breathing
• difficult, burning, or painful urination
• dizziness
• fainting
• fast heartbeat
• fever
• frequent urge to urinate
• heavy non-menstrual vaginal bleeding
• hoarseness
• increased clear or white vaginal discharge
• lower back or side pain
• noisy, rattling breathing
• pain in the back, ribs, arms, or legs
• painful or difficult urination
• pale skin
• rapid weight gain
• rapid, shallow breathing
• stopping of menstrual bleeding
• tightness in the chest
• tingling of the hands or feet
• troubled breathing at rest
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss

Less common side effects:

• abnormal growth filled with fluid or semisolid material
• black, tarry stools
• bleeding gums
• bloating
• blurred vision
• breast pain, redness, or swelling
• chest pain
• clear or bloody discharge from the nipple
• cough producing mucus
• dimpling of the breast skin
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck headache
• inverted nipple
• joint pain or stiffness
• large amount of cholesterol in the blood
• lump in the breast or under the arm
• nervousness
• persistent crusting or scaling of the nipple
• pinpoint red spots on the skin
• pounding in the ears
• skin rash or itching over the entire body
• slow heartbeat
• sore on the skin of the breast that does not heal
• stomach or pelvic discomfort, aching, or heaviness

Rare side effects:

• anxiety
• bluish color of the skin
• tenderness

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• vision problems
• loss of appetite
• yellowing of the skin or eyes
• unusual bruising or bleeding
• fever
• blisters
• rash
• swelling of the eyes, face, lips, tongue, throat, hands, arms, feet, ankles, or lower legs
• thirst
• muscle weakness
• restlessness

Tamoxifen may increase the risk that you will develop other cancers, including liver cancer. Talk to your doctor about this risk.

Tamoxifen may increase the risk that you will develop cataracts (clouding of the lens in the eye) that may need to be treated with surgery. Talk to your doctor about this risk.

Tamoxifen may cause other side effects. Call your doctor if you have any unusual problems while taking tamoxifen.

Symptoms of tamoxifen overdose may include:

• uncontrollable shaking of a part of the body
• unsteadiness
• dizziness

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