Adverse reactions to NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) and generally subside rapidly.
In patients treated with NOLVADEX (tamoxifen citrate) for metastatic breast cancer, the most frequent adverse reaction to NOLVADEX (tamoxifen citrate) 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.
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 NOLVADEX (tamoxifen citrate) therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.
|Adverse Reactions|| NOLVADEX (tamoxifen citrate) |
All Effects % of
| OVARIAN ABLATION |
% of Women
|Some women had more than one adverse reaction.|
Male Breast Cancer
NOLVADEX (tamoxifen citrate) is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) -treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with NOLVADEX (tamoxifen citrate) who had thrombotic events died.
|NSABP B-14 Study|
|Adverse Effect||% of Women|
| NOLVADEX |
| Placebo |
|Weight Loss ( > 5%)||23||18|
|Deep Vein Thrombosis||0.8||0.2|
|Defined as a platelet count of < 100,000/mm3|
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX (tamoxifen citrate) or placebo was administered for 2 years to women following mastectomy. When compared to placebo, NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) was 10% vs. 3% for placebo, an observation of borderline statistical significance.
In other adjuvant studies, Toronto and NOLVADEX (tamoxifen citrate) Adjuvant Trial Organization (NATO), women received either NOLVADEX (tamoxifen citrate) or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) vs. 0.2% for each in the untreated group.
Anastrozole Adjuvant Trial - Study of Anastrozole compared to NOLVADEX (tamoxifen citrate) for Adjuvant Treatment of Early Breast Cancer (see CLINICAL PHARMACOLOGY - Clinical Studies).
At a median follow-up of 33 months, the combination of anastrozole and NOLVADEX (tamoxifen citrate) did not demonstrate any efficacy benefit when compared to NOLVADEX (tamoxifen citrate) therapy given alone in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and NOLVADEX (tamoxifen citrate) 20 mg, respectively.
Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in the following table.
Adverse events occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment
|Body system and adverse event by COSTART-preferred term|| Anastrozole 1 mg |
(N = 3092)
| NOLVADEX 20 mg |
(N = 3094)
|Body as a whole|
|Asthenia||575 (19)||544 (18)|
|Pain||533 (17)||485 (16)|
|Back pain||321 (10)||309 (10)|
|Headache||314 (10)||249 (8)|
|Abdominal pain||271 (9)||276 (9)|
|Infection||285 (9)||276 (9)|
|Accidental injury||311 (10)||303 (10)|
|Flu syndrome||175 (6)||195 (6)|
|Chest pain||200 (7)||150 (5)|
|Neoplasm||162 (5)||144 (5)|
|Cyst||138 (5)||162 (5)|
|Vasodilatation||1104 (36)||1264 (41)|
|Hypertension||402 (13)||349 (11)|
|Nausea||343 (11)||335 (11)|
|Constipation||249 (8)||252 (8)|
|Diarrhea||265 (9)||216 (7)|
|Dyspepsia||206 (7)||169 (6)|
|Gastrointestinal disorder||210 (7)||158 (5)|
|Hemic and lymphatic|
|Lymphoedema||304 (10)||341 (11)|
|Anemia||113 (4)||159 (5)|
|Metabolic and nutritional|
|Peripheral edema||311 (10)||343 (11)|
|Weight gain||285 (9)||274 (9)|
|Hypercholesterolemia||278 (9)||108 (3.5)|
|Arthritis||512 (17)||445 (14)|
|Arthralgia||467 (15)||344 (11)|
|Osteoporosis||325 (11)||226 (7)|
|Fracture||315 (10)||209 (7)|
|Bone pain||201 (7)||185 (6)|
|Arthrosis||207 (7)||156 (5)|
|Joint Disorder||184 (6)||160 (5)|
|Myalgia||179 (6)||160 (5)|
|Depression||413 (13)||382 (12)|
|Insomnia||309 (10)||281 (9)|
|Dizziness||236 (8)||234 (8)|
|Anxiety||195 (6)||180 (6)|
|Paraesthesia||215 (7)||145 (5)|
|Pharyngitis||443 (14)||422 (14)|
|Cough increased||261 (8)||287 (9)|
|Dyspnea||234 (8)||237 (8)|
|Sinusitis||184 (6)||159 (5)|
|Bronchitis||167 (5)||153 (5)|
|Skin and appendages|
|Rash||333 (11)||387 (13)|
|Sweating||145 (5)||177 (6)|
|Cataract Specified||182 (6)||213 (7)|
|Leukorrhea||86 (3)||286 (9)|
|Urinary tract infection||244 (8)||313 (10)|
|Breast pain||251 (8)||169 (6)|
|Breast Neoplasm||164 (5)||139 (5)|
|Vulvovaginitis||194 (6)||150 (5)|
|Vaginal Hemorrhage†||122 (4)||180 (6)|
|Vaginitis||125 (4)||158 (5)|
| COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. |
N = Number of patients receiving the treatment.
A patient may have had more than 1 adverse event, including more than 1 adverse event in the same body system. † Vaginal Hemorrhage without further diagnosis.
The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.
Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see the following table).
Number (%) of Patients with Pre-Specified Adverse Event in the Anastrozole Adjuvant Trial1
| Anastrozole |
| NOLVADEX (tamoxifen citrate) |
|Hot Flashes||1104 (36)||1264 (41)||0.80||0.73 - 0.89|
|Musculoskeletal Events2||1100 (36)||911 (29)||1.32||1.19 - 1.47|
|Fatigue/Asthenia||575 (19)||544 (18)||1.07||0.94 - 1.22|
|Mood Disturbances||597 (19)||554 (18)||1.10||0.97 - 1.25|
|Nausea and Vomiting||393 (13)||384 (12)||1.03||0.88 - 1.19|
|All Fractures||315 (10)||209 (7)||1.57||1.30 - 1.88|
|Fractures of Spine, Hip, or Wrist||133 (4)||91 (3)||1.48||1.13 - 1.95|
|Wrist/Colles' fractures||67 (2)||50 (2)|
|Spine fractures||43 (1)||22 (1)|
|Hip fractures||28 (1)||26 (1)|
|Cataracts||182 (6)||213 (7)||0.85||0.69 - 1.04|
|Vaginal Bleeding||167 (5)||317 (10)||0.50||0.41 - 0.61|
|Ischemic Cardiovascular Disease||127 (4)||104 (3)||1.23||0.95 - 1.60|
|Vaginal Discharge||109 (4)||408 (13)||0.24||0.19 - 0.30|
|Venous Thromboembolic events||87 (3)||140 (5)||0.61||0.47 - 0.80|
|Deep Venous Thromboembolic||48 (2)||74 (2)||0.64||0.45 - 0.93|
|Ischemic Cerebrovascular Event||62 (2)||88 (3)||0.70||0.50 - 0.97|
|Endometrial Cancer3||4 (0.2)||13 (0.6)||0.31||0.10 - 0.94|
| 1Patients with multiple events in the same category are counted only once in that category. |
2Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.
3Percentages calculated based upon the numbers of patients with an intact uterus at baseline.
4The odds ratios < 1.00 favor Anastrozole and those > 1.00 favor NOLVADEX (tamoxifen citrate)
Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving NOLVADEX (tamoxifen citrate). Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving NOLVADEX (tamoxifen citrate) [209 (7%)]. Patients receiving anastrozole had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving NOLVADEX (tamoxifen citrate).
Patients receiving NOLVADEX (tamoxifen citrate) had a decrease in hypercholesterolemia (108 [3.5%]) compared to patients receiving anastrozole (278 [9%]). Angina pectoris was reported in 71 [2.3%] patients in the anastrozole arm and 51 [1.6%] patients in the NOLVADEX (tamoxifen citrate) arm; myocardial infarction was reported in 37 [1.2%] patients in the anastrozole arm and in 34 [1.1%] patients in the NOLVADEX (tamoxifen citrate) arm.
Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving NOLVADEX (tamoxifen citrate) had a mean increase in both lumbar spine and total hip BMD compared to baseline.
Ductal Carcinoma in Situ (DCIS)
The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with NOLVADEX (tamoxifen citrate).
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 NOLVADEX (tamoxifen citrate) group: endometrial cancer (33 cases in the NOLVADEX (tamoxifen citrate) group vs. 14 in the placebo group); pulmonary embolism (18 cases in the NOLVADEX (tamoxifen citrate) group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the NOLVADEX (tamoxifen citrate) group vs. 19 in the placebo group); stroke (34 cases in the NOLVADEX (tamoxifen citrate) group vs. 24 in the placebo group); cataract formation (540 cases in the NOLVADEX (tamoxifen citrate) group vs. 483 in the placebo group) and cataract surgery (101 cases in the NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) than placebo are shown.
|NSABP P-1 Trial: All Adverse Events % of Women|
| NOLVADEX |
| PLACEBO |
|Self Reported Symptoms||N=64411||N=64691|
| 1Number with Quality of Life Questionnaires |
2Number with Treatment Follow-up Forms
3Number with Adverse Drug Reaction Forms
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX (tamoxifen citrate) and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) and placebo therapy, respectively withdrew for non-medical reasons.
On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on NOLVADEX (tamoxifen citrate). Severe hot flashes occurred in 28% of women on placebo and 45% of women on NOLVADEX (tamoxifen citrate). Vaginal discharge occurred in 35% and 55% of women on placebo and NOLVADEX (tamoxifen citrate) respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms.
Pediatric Patients - McCune-Albright Syndrome
Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with NOLVADEX (tamoxifen citrate) for long-term effects is recommended. The safety and efficacy of NOLVADEX (tamoxifen citrate) 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 (tamoxifen citrate) therapy in girls have not been established.
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 NOLVADEX (tamoxifen citrate) 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 NOLVADEX (tamoxifen citrate) (see PRECAUTIONS- Drug/Laboratory Testing Interactions section).
Read the entire FDA prescribing information for Nolvadex (Tamoxifen Citrate)
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