SOLTAMOX SIDE EFFECTS

Last updated on MDtodate: 10/11/2022

SIDE EFFECTS

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Uterine malignancies Thromboembolic events
• Embryo-Fetal Toxicity
• Liver cancer

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions In Patients With Metastatic Breast Cancer

In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction was hot flashes. Other adverse reactions which were seen less commonly are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.

Increased bone, tumor pain and local disease flare have occurred. 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 occurred, the bone pain or disease flares were seen shortly after starting tamoxifen and generally subsided rapidly.

Premenopausal Women With Metastatic Breast Cancer

Table 1 summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials that compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Table 1: Adverse Reactions (frequency ≥2% in either arm) from Trials Comparing Tamoxifen to Ovarian Ablation in Premenopausal Women with Metastatic Breast Cancer

	% of Women
	Tamoxifen N=104	Ovarian Ablation N=100
Adverse Reactions*
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
* Some women had more than one adverse reaction.

 

Adverse Reactions In 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 per day or placebo following primary surgery. Table 2 presents the most common adverse reactions (mean follow-up of approximately 6.9 years) that were more common on tamoxifen than placebo.

Table 2: Most Common Adverse Reactions in Women with Axillary Node-Negative Breast Cancer (Study NSABP B-14)

	% of women
	Tamoxifen N = 1,422	Placebo 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
* Defined as a platelet count of < 100,000/mm³ **Two of the tamoxifen-treated patients 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 higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the two treatment groups with the exception of thrombocytopenia, where the incidence for tamoxifen was 10% vs. 3% for placebo.

In other adjuvant studies [the Toronto study 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 (ATAC: Arimidex, Tamoxifen, Alone Or In Combination) – Study Of Anastrozole Compared To Tamoxifen For Adjuvant Treatment Of Early Breast Cancer

At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate an efficacy benefit when compared to tamoxifen monotherapy in all patients as well as in the hormone receptorpositive subpopulation. The combination 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 monotherapy, respectively.

Adverse reactions occurring with an incidence of at least 5% in either single-drug treatment group during treatment or within 14 days of the end of treatment are presented in Table 3.

Table 3: Adverse Reactions Occurring with an Incidence of at Least 5% in Either Single-Drug Treatment Group During Treatment or Within 14 Days of the End of Treatment in the ATAC Trial

Body system and adverse reactions by COSTART-preferred term*	% of Women
	Tamoxifen N = 3,094	Anastrozole N = 3,092
Body as a whole
Asthenia	18	19
Pain	16	17
Back pain	10	10
Accidental injury	10	10
Abdominal pain	9	9
Infection	9	9
Headache	8	10
Flu syndrome	6	6
Cyst	5	5
Chest pain	5	7
Neoplasm	5	5
Cardiovascular
Vasodilatation	41	36
Hypertension	11	13
Digestive
Nausea	11	11
Constipation	8	8
Diarrhea	7	9
Dyspepsia	6	7
Gastrointestinal disorder	5	7
Hemic and lymphatic
Lymphedema	11	10
Anemia	5	4
Metabolic and nutritional
Peripheral edema	11	10
Weight gain	9	9
Hypercholesterolemia	3	9
Musculoskeletal
Arthritis	14	17
Arthralgia	11	15
Osteoporosis	7	11
Fracture	7	10
Bone pain	6	7
Joint disorder	5	6
Myalgia	5	6
Arthrosis	5	7
Nervous system
Depression	12	13
Insomnia	9	10
Dizziness	8	8
Anxiety	6	6
Paresthesia	5	7
Respiratory
Pharyngitis	14	14
Cough increased	9	8
Dyspnea	8	8
Sinusitis	5	6
Bronchitis	5	5
Skin and appendages
Rash	13	11
Sweating	6	5
Special senses
Cataract specified	7	6
Urogenital
Urinary tract infection	10	8
Leukorrhea	9	3
Vaginal hemorrhage†	6	4
Breast pain	6	8
Vaginitis	5	4
Vulvovaginitis	5	6
Breast neoplasm	5	5
* COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms. A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. † Vaginal hemorrhage without further diagnosis

 

Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis in the ATAC trial, based on the known pharmacologic properties and safety profiles of the two drugs (Table 4).

Table 4: Percentage of Patients with Pre-Specified Adverse Reactions in the ATAC Trial^a

	% of Women		Odds Ratioc	95% CI
	Tamoxifen N = 3,094	Anastrozole N = 3,092
Hot flashes	41	36	0.80	0.73 to 0.89
Musculoskeletal eventsb	29	36	1.32	1.19 to 1.47
Mood disturbances	18	19	1.10	0.97 to 1.25
Fatigue/asthenia	18	19	1.07	0.94 to 1.22
Vaginal discharge	13	4	0.24	0.19 to 0.30
Nausea and vomiting	12	13	1.03	0.88 to 1.19
Vaginal bleeding	10	5	0.50	0.41 to 0.61
Cataracts	7	6	0.85	0.69 to 1.04
All fractures	7	10	1.57	1.30 to 1.88
Fractures of spine, hip, or wrist	3	4	1.48	1.13 to 1.95
Wrist/Colles’ fractures	2	2
Hip fractures	1	1
Spine fractures	1	1
Venous thromboembolic events	5	3	0.61	0.47 to 0.80
Deep venous thromboembolic events	2	2	0.64	0.45 to 0.93
Ischemic cerebrovascular events	3	2	0.70	0.50 to 0.97
Ischemic cardiovascular	3	4	1.23	0.95 to 1.60
disease
Endometrial cancerd	0.6	0.2	0.31	0.10 to 0.94
a Patients with multiple events in the same category are counted only once in that category. b Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. c The odds ratios <1 favor anastrozole and those >1 favor tamoxifen. d Percentages calculated based upon the numbers of women who had not undergone hysterectomy at baseline.

 

Adverse Reactions In Ductal Carcinoma In Situ

The types and frequency of adverse reactions in the NSABP B-24 trial in women with DCIS were consistent with those observed in the other adjuvant trials conducted with tamoxifen.

Adverse Reactions In Women At High Risk For Breast Cancer

In the NSABP P-1 trial, there was an increase in five serious adverse reactions 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).

Table 5 presents the adverse reactions observed in NSABP P-1 by treatment arm. Only adverse reactions more common on tamoxifen than placebo are shown.

Table 5: Most Common Adverse Reactions in Women at High Risk for Breast Cancer (Study NSABP P-1)

	% of Women
	Tamoxifen N = 6,681	Placebo N = 6,707
Self-Reported Symptoms	N = 6,441a	N = 6,469a
Hot flashes	80	68
Vaginal discharge	55	35
Vaginal bleeding	23	22
Laboratory Abnormalities	N = 6,520b	N = 6,535b
Platelets decreased	0.7	0.3
Adverse Reactions	N = 6,492c	N = 6,484c
Mood changes	11.6	10.8
Infection/sepsis	6.0	5.1
Constipation	4.4	3.2
Skin changes	5.6	4.7
Alopecia	5.2	4.4
Allergy	2.5	2.1
a Number with quality of life questionnaires b Number with treatment follow-up forms c Number with adverse drug reaction forms

 

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 including the following: hot flashes (3.1% vs. 1.5%, respectively) and vaginal discharge (0.5% vs. 0.1% respectively).

Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge was severe in 4.5% on placebo and 12.3% on tamoxifen.

SOLTAMOX-related Adverse Reactions

In a single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal women, throat irritation was reported by 3 of 60 evaluable subjects (5%) in the SOLTAMOX treatment group while none of the subjects in the tamoxifen citrate tablet group reported this event. All cases were mild, occurred within an hour after dosing, and resolved within 24 hours.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tamoxifen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Disorders: Erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid

Respiratory, Thoracic, Mediastinal Disorders: Interstitial pneumonitis

Immune System Disorders: Hypersensitivity reactions including angioedema; in some of these cases, the time to onset was more than one year.

Gastrointestinal Disorders: Elevation of serum triglyceride levels, in some cases with pancreatitis

Men With Metastatic Breast Cancer

Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. In oligospermic males treated with tamoxifen, LH, FSH, testosterone, and estrogen levels were elevated, with no reported associated clinical changes.a