Side Effects of Soltamox (tamoxifen)

Soltamox (tamoxifen) is an anti-estrogen that prevents the effects of estrogens on tissues and is used to treat invasive breast cancer in men and women, the most common type of breast cancer, following surgery and/or radiation and to prevent invasive breast cancer in women at high risk for developing it. 

Soltamox also is used to treat women following surgery and radiation for a less common type of breast cancer called ductal carcinoma in situ (DCIS or intraductal carcinoma). 

Women who have had DCIS are at high risk for developing invasive breast cancer at a later date, and Soltamox prevents development of the invasive cancer in almost half of the women during the first five years of treatment. Occasionally, Soltamox is used to stimulate ovulation.

Common side effects of Soltamox include:

• hot flashes,
• weight loss,
• abnormal or absence of menstrual periods,
• vaginal discharge,
• vaginal bleeding,
• lightheadedness,
• dizziness,
• headache,
• vomiting,
• nausea,
• cough,
• fatigue,
• fluid retention,
• bone pain,
• cataracts, and
• depression.

Serious side effects of Soltamox include blood clots leading to:

• deep vein thrombosis (DVT) and pulmonary embolism (PE),
• abnormalities of liver tests,
• reduced white blood cells,
• red blood cells, and
• platelets. Reduced platelets can lead to bleeding. 

Drug interactions of Soltamox include warfarin, because Soltamox increases its blood-thinning effects.

Soltamox reduces blood levels of letrozole and anastrozole.

Phenobarbital and rifampin may reduce blood levels of Soltamox by increasing the breakdown of Soltamox.

Soltamox should not be used during pregnancy because it can harm a fetus. It is unknown if Soltamox is excreted in breast milk. Soltamox causes a reduction in milk production. Women taking Soltamox should not breastfeed.

WARNING

Uterine malignancies, stroke, and pulmonary embolism were reported when tamoxifen was used for risk-reduction in women with ductal carcinoma in situ and women at high risk for breast cancer.

The most common side effects associated with tamoxifen are:

• Hot flashes
• Weight loss
• Abnormal or absence of menstrual periods
• Vaginal discharge
• Vaginal bleeding
• Lightheadedness
• Dizziness
• Headache
• Vomiting
• Nausea
• Cough
• Fatigue
• Fluid retention
• Bone pain
• Cataracts
• Depression

Serious side effects include:

• Tamoxifen is associated with blood clots leading to deep vein thrombosis and pulmonary embolism.
• Tamoxifen can cause abnormalities of liver tests, reduced white blood cells, red blood cells, and platelets. Reduced platelets can lead to bleeding. Patients should keep appointments for blood work to monitor for these side effects. Patients should report any suspected side effects immediately, especially bleeding and yellowing of the skin.

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

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)

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

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

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)

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.

Aromatase Inhibitors

Anastrozole

The combination of anastrozole and tamoxifen did not demonstrate any benefit when compared to tamoxifen alone and should be avoided in all patients. In the ATAC trial, co-administration of anastrozole and tamoxifen in breast cancer patients reduced the anastrozole plasma concentration by 27% compared to that achieved with anastrozole alone. The tamoxifen concentration was not altered.

Letrozole

The concomitant use of letrozole with tamoxifen is not recommended because the efficacy of the combination in the adjuvant treatment of breast cancer has not been established. Tamoxifen reduced the plasma concentration of letrozole by 38% when these drugs were co-administered.

Warfarin

A marked increase in anticoagulant effect may occur when tamoxifen is used in combination with warfarin. Closely monitor coagulation indices in patients who are taking tamoxifen for either the treatment of metastatic breast cancer or as adjuvant therapy who require concomitant use of warfarin.

Inducers Of CYP3A4

Strong CYP3A4 inducers should not be used with tamoxifen. Strong CYP3A4 inducers (e.g., rifampin) reduce tamoxifen AUC and Cmax.

Strong Inhibitors Of CYP2D6

The impact on the efficacy of tamoxifen with co-administration of strong CYP2D6 inhibitors (e.g., paroxetine) is not well established. Some studies have shown that the efficacy of tamoxifen may be reduced when the drugs are co-administered as a result of reduced levels of potent active metabolites of tamoxifen. However, other studies have failed to demonstrate such an effect.

Drug-Laboratory Test Interactions

There are postmarketing reports of T4 elevations in postmenopausal patients taking tamoxifen that may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism.

Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been seen in postmenopausal patients taking tamoxifen.