Tamoxifen Citrate

10 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX (tamoxifen citrate) 600 debossed on one side and a cameo debossed on the other side) are supplied in bottles of 60 tablets. NDC 0310-0600-60.

20 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 20 mg of tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX (tamoxifen citrate) 604 debossed on one side and a cameo debossed on the other side) are supplied in bottles of 30 tablets. NDC 0310-0604-30.

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

*Coumadin® is a registered trademark of Bristol-Myers Squibb Pharmaceuticals. All other trademarks are the property of the AstraZeneca group, AstraZeneca Pharmaceuticals LP Wilmington, Delaware 19850-5437. Rev 09-27-05. FDA revision date: 3/9/2006

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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after NOLVADEX (tamoxifen citrate) was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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.

Tamoxifen blocks the actions of estrogen, a female hormone. Certain types of breast cancer require estrogen to grow.

Tamoxifen is used to treat some types of breast cancer in men and women. Tamoxifen is also used to lower a woman's chance of developing breast cancer if she has a high risk (such as a family history of breast cancer).

Tamoxifen may also be used for purposes not listed in this medication guide.

Do not use tamoxifen if you are pregnant. It could harm the unborn baby. Use a barrier form of birth control (such as a condom or diaphragm with spermicide) while you are using this medication and for at least 2 months after your treatment ends.

You should not use tamoxifen if you are allergic to it, or if you have a history of blood clots in your veins or your lungs, or if you are also taking a blood thinner such as warfarin (Coumadin).

Before using tamoxifen, tell your doctor if you have liver disease, high triglycerides (a type of fat in the blood), a history of cataract, or a history of stroke or blood clot. Also tell your doctor if you if you are receiving chemotherapy or radiation treatment.

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.

Taking tamoxifen may increase your risk of uterine cancer, stroke, or a blood clot in the lung, which can be fatal. Talk with your doctor about your specific risks in taking this medication.

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.

Avoid eating soy or soy products without first asking your doctor.

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.

In one single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal female volunteers, throat irritation was reported by 3 of 60 evaluable subjects (5.0%) in the SOLTAMOX™ (tamoxifen citrate) treatment groups while none of the subjects in the tamoxifen reference group reported this event. All events were mild and occurred within an hour after dosing. All events were resolved within 24 hours.

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.

NSABPB-14 Study

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.

Ductal Carcinoma in Situ (DCIS)

The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with tamoxifen.

Reduction in Breast Cancer Incidence in High Risk Women

In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group) (See WARNINGS and Table 3 in CLINICAL PHARMACOLOGY).

The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on tamoxifen than placebo are shown.

NSABP P-l Trial: All Adverse Events

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively, withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).

In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen and placebo therapy, respectively, withdrew for non-medical reasons.

On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms.

Postmarketing Experience

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen (see PRECAUTIONS, Drug/Laboratory Testing Interactions section).

Read the entire FDA prescribing information for Soltamox (Tamoxifen Citrate)

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.128

Contraindications

• Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

• When used in women with DCIS and women at high risk for breast cancer, history of DVT or pulmonary embolism.a

• When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.a 278 293 309

Warnings/Precautions

Warnings

Hypercalcemia reported in patients with metastatic breast cancer who have bone metastases.128 129 If hypercalcemia occurs, take appropriate measures; if severe, discontinue tamoxifen.128

Increased incidence of uterine malignancies, sometimes fatal, reported.128 330 Most uterine malignancies have been classified as adenocarcinoma of the endometrium; rare uterine sarcomas also reported.128 330 (See Boxed Warning.) Gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be promptly evaluated.128 163 183

Endometrial changes, including hyperplasias and polyps, endometriosis and uterine fibroids reported.128 180 258 259 274 Ovarian cysts reported in a small number of premenopausal women with advanced breast cancer.128

Increased incidence of thromboembolic events, including DVT128 293 and pulmonary embolism; 269 270 293 stroke also reported.128 269 277 293 Some cases of stroke and pulmonary emboli have been fatal.128 (See Boxed Warning.) Concomitant use with chemotherapy may increase incidence of these events.128

Liver cancer reported.128

Changes in AST, ALT, bilirubin and/or alkaline phosphatase concentrations reported; severe hepatic abnormalities including fatty changes in the liver, cholestasis, hepatitis, and hepatic necrosis (some fatal) reported rarely.128

Visual disturbances, decrement in color vision perception, corneal changes, cataracts, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy reported.128 190 191 192 193 258 268 326

May cause fetal harm.128 If inadvertently used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard, including possible long-term risk of a diethylstilbestrol-like syndrome.128

General Precautions

Thrombocytopenia, neutropenia, pancytopenia, and leukopenia reported; caution in patients with leukopenia or thrombocytopenia.128 Periodic CBCs, including platelet count recommended.128

Specific Populations

Category D.128 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether tamoxifen is distributed into milk.128 Discontinue nursing or the drug because of potential risk to nursing infant.128

Safety and efficacy in girls 2–10 years of age with Albright’s syndrome and precocious puberty not studied beyond 1 year; long-term effects not established and continued monitoring recommended.a (See Special Populations under Pharmacokinetics.)

No substantial differences in safety and efficacy relative to younger adults.a

Common Adverse Effects

Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128

A substrate of CYP3A, 2C9, 2D6.a

Effect of tamoxifen on drugs that require mixed function oxidases for activation unknown.a

Cytotoxic Agents

Increased risk of thromboembolic events.128

Specific Drugs