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Soltamox (Tamoxifen Citrate) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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™ 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.

* Some women had more than one adverse reaction
  TAMOXIFEN OVARIAN ABLATION
  All effects % of Women All Effects % of Women
Adverse Reactions n = 104 n = 100
Flush 33 46
Amenorrhea 16 69
Altered Menses 13 5
Oligomenorrhea 9 1
Bone Pain 6 6
Menstrual Disorder 6 4
Nausea 5 4
Cough/Coughing 4 1
Edema 4 1
Fatigue 4 1
Musculoskeletal Pain 3 0
Pain 3 4
Ovarian Cyst(s) 3 2
Depression 2 2
Abdominal Cramps 1 2
Anorexia 1 2

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.

NSABP B-14 Study
* Defined as a platelet count of < 100,000/mm3
  % of Women
Adverse Effect TAMOXIFEN PLACEBO
  (n = 1,422) (n = 1,437)
Hot Flashes 64 48
Fluid Retention 32 30
Vaginal Discharge 30 15
Nausea 26 24
Irregular Menses 25 19
Weight Loss (> 5%) 23 18
Skin Changes 19 15
Increased SGOT 5 3
Increased Bilirubin 2 1
Increased Creatinine 2 1
Thrombocytopenia* 2 1
Thrombotic Events    
Deep-Vein Thrombosis 0.8 0.2
Pulmonary Embolism 0.5 0.2
Superficial Phlebitis 0.4 0.0

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 (193% vs. 83% 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 103% vs. 3% for placebo, an observation of borderline statistical significance.

In other adjuvant studies, Toronto and tamoxifen Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group.

Anastrozole Adjuvant Trial – Study of Anastrozole Compared to Tamoxifen 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 tamoxifen did not demonstrate any efficacy benefit when compared to tamoxifen 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 tamoxifen 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
* 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
† COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.
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.
N = Number of patients receiving the treatment.
**The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.
Body system and adverse
event by COSTART-preferred
term*,
   
  ANASTROZOLE 1 mg
(N = 3,092)
TAMOXIFEN 20 mg
(N = 3,094)
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)
Cardiovascular    
Vasodilatation 1,104 (36) 1,264 (41)
Hypertension 402 (13) 349 (11)
Digestive    
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)
Musculoskeletal    
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)
Nervous system    
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)
Respiratory    
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)
Special Senses    
Cataract specified 182 (6) 213 (7)
Urogenital    
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)

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 Trial*
* Patients with multiple events in the same category are counted only once in that category.
The odds ratios < 1.00 favor anastrozole and those > 1.00 favor tamoxifen
Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.
§ Percentages calculated based upon the numbers of patients with an intact uterus at baseline.
  Anastrozole
N = 3,092
(%)
Tamoxifen
N = 3,094
(%)
Odds-Ratio† 95% CI†
Hot Flashes 1,104 (36) 1,264 (41) 0.80 0.73 to 0.89
Musculoskeletal Events‡ 1,100 (36) 911 (29) 1.32 1.19 to 1.47
Fatigue/Asthenia 575 (19) 544 (18) 1.07 0.94 to 1.22
Mood Disturbances 597 (19) 554 (18) 1.10 0.97 to 1.25
Nausea and Vomiting 393 (13) 384 (12) 1.03 0.88 to 1.19
All Fractures 315 (10) 209 (7) 1.57 1.30 to 1.88
Fractures of Spine, Hip, or Wrist 133 (4) 91 (3) 1.48 1.13 to 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 to 1.04
Vaginal Bleeding 167 (5) 317 (10) 0.50 0.41 to 0.61
Ischemic Cardiovascular Disease 127 (4) 104 (3) 1.23 0.95 to 1.60
Vaginal Discharge 109 (4) 408 (13) 0.24 0.19 to 0.30
Venous Thromboembolic Events 87 (3) 140 (5) 0.61 0.47 to 0.80
Deep Venous Thromboembolic Events 48 (2) 74 (2) 0.64 0.45 to 0.93
Ischemic Cerebrovascular Event 62 (2) 88 (3) 0.70 0.50 to 0.97
Endometrial Cancer§ 4 (0.2) 13 (0.6) 0.31 0.10 to 0.94

Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. 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 tamoxifen [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 receivingn tamoxifen.

Patients receiving tamoxifen 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 tamoxifen arm; myocardial infarction was reported in 37 (1.2%) patients in the anastrozole arm and in 34 (1.1%) patients in the tamoxifen arm.

Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen 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 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-1 Trial: All Adverse Events
* Number with Quality of Life Questionnaires
Number with Treatment Follow-up Forms
Number with Adverse Drug Reaction Forms
  % of Women
  TAMOXIFEN PLACEBO
  N = 6,681 N = 6,707
Self Reported Symptoms N = 6,441* N = 6,469*
Hot Flashes 80 68
Vaginal Discharges 55 35
Vaginal Bleeding 23 22
Laboratory Abnormalities N = 6,520 N = 6,535
Platelets Decreased 0.7 0.3
Adverse Effects N = 6,492 N = 6,484
Other Toxicities    
Mood 11.6 10.8
Infection/Sepsis 6.0 5.1
Constipation 4.4 3.2
Alopecia 5.2 4.4
Skin 5.6 4.7
Allergy 2.5 2.1

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.

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 tamoxifen (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with tamoxifen for long-term effects is recommended. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright syndrome and precocious puberty have not been studied beyond 1 year of treatment. The long-term effects of tamoxifen therapy in girls have not been established.

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).

Drug label data at the top of this Page last updated: 2012-09-12

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