DESCRIPTION
Mechanism of Action
• Nonsteroidal antiestrogen with weak estrogen agonist effects.
• Competes with estrogen for binding to ERs. Binding of tamoxifen to
ER leads to ER dimerization. The tamoxifen-bound ER dimer is
transported to the nucleus, where it binds to DNA sequences
referred to as ER elements. This interaction results in inhibition of
critical transcriptional processes and signal transduction pathways
that are required for cellular growth and proliferation.
• Cell cycle–specific agent that blocks cells in the mid-G1 phase of the
cell cycle. Effect may be mediated by cyclin D.
• Stimulates the secretion of transforming growth factor-b (TGF-b),
which then acts to inhibit the expression and/or activity of TGF-α and
IGF-1, two genes that are involved in cell growth and proliferation.
Mechanism of Resistance
• Decreased expression of ER.
• Mutations in the ER leading to decreased binding affinity to tamoxifen.
• Overexpression of growth factor receptors, such as as EGFR, HER2/neu,
IGF-1R, or TGF-b that counteract the inhibitory effects of tamoxifen.
• Presence of ESR1 mutations.
Absorption
Rapidly and completely absorbed in the GI tract. Peak plasma levels are
achieved within 4–6 hours after oral administration.
Distribution
Distributes to most body tissues, especially in those expressing estrogen
receptors. Present in very low concentrations in CSF. Nearly all of drug is
bound to plasma proteins.
Metabolism
Extensively metabolized by liver cytochrome P450 enzymes after oral administration.
The main metabolite, N-desmethyl tamoxifen, has biologic activity similar
to that of the parent drug. Both tamoxifen and its metabolites are excreted
primarily (75%) in feces with minimal clearance in urine. The terminal half-lives
of tamoxifen and its metabolites are relatively long, approaching 7–14 days.
Indications
1. Adjuvant therapy in axillary node-negative breast cancer following
surgical resection.
2. Adjuvant therapy in axillary node-positive breast cancer
in postmenopausal women following surgical resection.
3. Adjuvant therapy in women with ductal carcinoma in situ (DCIS)
after surgical resection and radiation therapy.
4. Metastatic breast cancer in women and men.
5. Approved as a chemopreventive agent for women at high risk for
breast cancer. “High-risk” women are defined as women .35 years
and with a 5-year predicted risk of breast
cancer $1.67%, according to the Gail model.
6. Endometrial cancer.
Dosage Range
Recommended dose for treatment of breast cancer patients is 20 mg PO
every day.
Drug Interaction 1
Warfarin—Tamoxifen can inhibit metabolism of warfarin by the liver
P450 system leading to increased anticoagulant effect. Coagulation parameters,
including PT and INR, must be closely monitored, and dose adjustments
may be required.
Drug Interaction 2
Drugs activated by liver P450 system—Tamoxifen and its metabolites are
potent inhibitors of hepatic P450 enzymes and may inhibit the metabolic
activation of drugs utilizing this pathway, including cyclophosphamide.
Chemotherapeutic and Biologic Drugs 399
Drug Interaction 3
Drugs metabolized by liver P450 system—Tamoxifen and its metabolites
are potent inhibitors of hepatic P450 enzymes and may inhibit the metabolism
of various drugs, including erythromycin, calcium channel blockers,
and cyclosporine.
Drug Interaction 4
Antidepressants that act as selective serotonin reuptake inhibitors (SSRIs)
or selective noradrenergic reuptake inhibitors (SNRIs)—Drugs such as paroxetine,
fluoxetine, bupropion, duloxetine, and sertraline are inhibitors of
CYP2D6, which can then interfere and inhibit tamoxifen metabolism, resulting
in lower blood levels of the active tamoxifen metabolites.
Drug Interaction 5
Antipsychotics—Drugs such as thioridazine, perphenazine, and pimozide
are inhibitors of CYP2D6, which can then interfere and inhibit tamoxifen
metabolism, resulting in lower blood levels of the active tamoxifen
metabolites.
Drug Interaction 6
Drugs such as cimetidine, quinidine, ticlopidine, and terfenadine are
inhibitors of CYP2D6, which can then interfere and inhibit tamoxifen
 metabolism, resulting in lower blood levels of the active tamoxifen metabolites.
Special Considerations
1. Instruct patients to notify physician about menstrual irregularities,
abnormal vaginal bleeding, and pelvic pain and/or discomfort while
on therapy.
2. Patients should have routine follow-up with a gynecologist as tamoxifen
therapy is associated with an increased risk of endometrial hyperplasia,
polyps, and endometrial cancer.
3. Use with caution in patients with abnormal liver function as there
may be an increased risk of drug accumulation resulting in toxicity.
4. Use with caution in patients with either personal history or family history
of thromboembolic disease or hypercoagulable states as tamoxifen
is associated with an increased risk of thromboembolic events.
Tamoxifen therapy is associated with antithrombin III deficiency.
5. Initiation of treatment with tamoxifen may induce a transient tumor
flare. Tamoxifen should not be given in patients with impending ureteral
obstruction, spinal cord compression, or in those with extensive
painful bone metastases.
6. Premenopausal patients should be warned about the possibility of
developing menopausal symptoms with tamoxifen therapy.
T 7. Monitor CBC during therapy with tamoxifen as myelosuppression
can occur, albeit rarely.
8. Testing for CYP2D6 is recommended prior to initiation of tamoxifen
therapy. Up to 10% of patients are poor metabolizers of tamoxifen based
on CYP2D6 alleles, which might result in reduced clinical efficacy.
9. Consider using citalopram, escitalopram, fluvoxamine, mirtazapine,
and venlafaxine if an antidepressant is required during treatment
with tamoxifen.
10. Avoid the use of medications that inhibit the CYP2D6 system.
11. Pregnancy category D. Breastfeeding should be avoided.
Toxicity 1
Menopausal symptoms, including hot flashes, nausea, vomiting, vaginal
bleeding, and menstrual irregularities. Vaginal discharge and vaginal dryness
also observed.
Toxicity 2
Fluid retention and peripheral edema observed in about 30% of patients.
Toxicity 3
Tumor flare usually occurs within the first 2 weeks of starting therapy.
May observe increased bone pain, urinary retention, back pain with spinal
cord compression, and/or hypercalcemia.
Toxicity 4
Headache, lethargy, dizziness occur rarely. Visual disturbances, including
cataracts, retinopathy, and decreased visual acuity, have been described.
Toxicity 5
Skin rash, pruritus, hair thinning, and/or partial hair loss.
Toxicity 6
Myelosuppression is rare, with transient thrombocytopenia and leukopenia.
Usually resolves after the first week of treatment.
Toxicity 7
Thromboembolic complications, including deep vein thrombosis, pulmonary
embolism, and superficial phlebitis. Incidence of thromboembolic events
may be increased when tamoxifen is given concomitantly with chemotherapy.
Toxicity 8
Elevations in serum triglycerides.
Toxicity 9
Increased incidence of endometrial hyperplasia, polyps, and endometrial
cancer.
SPECIFICATION
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