Tugas Kanker Oleh Bu Ayu

The mechanisms by which cancers occur are incompletely understood.
A cancer is
thought to develop from a cell in which the normal mechanisms that control cell growth
and proliferation are altered. Current evidence supports the concept of carcinogenesis
as a multistage process that is genetically regulated.2,3 The first step in this process is
initiation, which requires exposure of normal cells to carcinogens. These carcinogens
produce genetic alterations that, if not repaired, results in irreversible cellular changes.
The changed cell may subsequently have an altered response to their environment that
provides a selective growth advantage and permits the development of a clonal
population of cancer cells. During the second step, known as promotion, carcinogens or
other factors alter the environment to favor growth of the altered cell population
compared to normal cells. Promotion could be affected by chemoprevention strategies
(strategies to lower cancer risk), including changes in lifestyle and diet. At some point,
the altered cell becomes cancerous (conversion or transformation). Depending on the
cancer, 5 to 20 years may elapse between the initiation and the development of a
clinically detectable cancer. The final stage, called progression, involves further genetic
alterations that lead to increased cell proliferation. The critical elements of this phase
include invasion into local tissues and the development of metastases.
Substances that may act as carcinogens include a myriad of chemical, physical, and
biologic agents.2 Chemical exposures may occur by occupational and environmental
means or by lifestyle habits. Some chemicals associated with cancer include aniline dye,
asbestos, and benzene. Aniline dye is a known cause of bladder cancer; benzene is a
known cause of leukemia and asbestos is a known cause of mesothelioma. Some drugs
and hormones used for therapeutic purposes are also classified as carcinogens (Table
127-1). Physical agents that act as carcinogens include ionizing radiation and ultraviolet
light; radiation induces mutations by forming free radicals that damage
deoxyribonucleic acid (DNA) and other cellular components. Biologic agents that are
associated with certain cancers, include natural compounds (ie, viruses) or pollutants.
The Epstein-Barr virus (EBV) may be an important factor in the initiation of Burkitt
lymphoma. Likewise, infection with human papilloma virus (HPV) is a cause of cervical
and head and neck cancers. Hereditary factors, age, and gender may also contribute to
the development of cancer.
DIPIRO 2017
TABLE 127-1 Selected Drugs and Hormones Known to Cause Cancer in Humans
Drug or Hormone Type of Cancer
Alkylating agents (eg, chlorambucil, mechlorethamine,
melphalan, and nitrosoureas)
Leukemia
Anabolic steroids Liver
Analgesics containing phenacetin Renal, urinary bladder
Anthracyclines (eg, doxorubicin) Leukemia
Antiestrogens (tamoxifen) Endometrium
Coal tars (topical) Skin
Nonsteroidal estrogens (diethylstilbestrol)
Vagina or cervix, endometrium,
breast, testes
Steroidal estrogens (estrogen replacement therapy, oral
contraceptives)
Endometrium, breast, liver
Epipodophyllotoxins (etoposide, teniposide) Leukemia
Immunosuppressive drugs (cyclosporine, azathioprine) Lymphoma, skin
Drug or Hormone Type of Cancer

Oxazaphosphorines (cyclophosphamide, ifosfamide) Urinary bladder
DIPIRO 2O11
Adjuvant Endocrine Therapy
Hormonal therapies that have been studied in the treatment of primary or early stage breast
cancer include tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone-
releasing hormone (LHRH) agonists and aromatase inhibitors. Choice of agent(s) depends on
menopausal status and is based on a multitude of clinical trials completed in this setting that
establish different roles for different therapies.
Tamoxifen was traditionally the gold standard adjuvant hormonal therapy and has been used in
the adjuvant setting for more than three decades. Tamoxifen is antiestrogenic in breast cancer
cells, but it appears to have estrogenic properties in other tissues and organs.126,127 More recent
studies show that tamoxifen and other similar drugs have many estrogenic and antiestrogenic
effects that depend on the tissue and the gene in question, and they are more appropriately called
selective estrogen receptor modulators (SERMs). Women receiving adjuvant tamoxifen therapy
have reduced risk of recurrence and mortality as compared with women not receiving adjuvant
tamoxifen therapy.5 This observation, coupled with evidence of tolerability for tamoxifen,
including beneficial estrogenic effects on the lipid profile and bone density, led to tamoxifen
being the hormonal agent of choice for both pre- and postmenopausal women when compared
with older, more toxic therapies (e.g., megestrol acetate). Premenopausal patients may derive
equivalent benefit from ovarian ablation via surgery or administration of LHRH agonists when
compared with tamoxifen.5 In the United States, tamoxifen is generally considered the adjuvant
hormonal therapy of choice for premenopausal women. However, many ongoing clinical trials
are investigating the use of the LHRH agonists or oophorectomy instead of tamoxifen or in
addition to tamoxifen or aromatase inhibitors in this group of women.
The optimal dose of tamoxifen is unclear. The EBCTCG overview showed that more (up to 40
mg/day) is not necessarily better for response rates.5 Lower doses of tamoxifen (less than 20
mg/day) may be effective, but no clinical trials have addressed this question. Therefore the
current recommended dose for tamoxifen in the adjuvant, metastatic, and preventive settings is
20 mg/day. Because tamoxifen has a long biologic half-life, it can be administered as a single
daily dose. Adjuvant tamoxifen therapy is generally initiated shortly after surgery or as soon as
pathology results are known and the decision to administer tamoxifen as adjuvant therapy is
made.
When adjuvant tamoxifen is given with chemotherapy, it should be given after chemotherapy is
completed. This recommendation is based on laboratory and clinical evidence from a phase III
trial suggesting tamoxifen administered concurrently with chemotherapy may antagonize the
beneficial effect of chemotherapy.128 In the phase III clinical trial, administration of sequential
tamoxifen resulted in a marginally superior DFS as compared to concurrent use of tamoxifen
with chemotherapy (HR, 0.84; 95% CI, 0.70-1.01; P = 0.061).128 Some clinicians also advocate
the initiation of tamoxifen following completion of radiation therapy, but this subject is very
controversial and few trials have addressed the issue of concurrent versus sequential hormone
therapy and radiation therapy.
The optimal duration of tamoxifen therapy in the adjuvant setting is currently 5 years. Studies of
prolonged administration (e.g., 10 years) have failed to demonstrate any advantage and in fact
may be associated with a slightly worse survival.129 Other clinical trials investigating durations
of tamoxifen use longer than 5 years are ongoing.
The pharmacologic disposition of tamoxifen in humans is very complex and has only recently
been elucidated (Fig. 136–6). Tamoxifen is now considered to be a prodrug. Although the parent
compound has significant clinical activity, tamoxifen is metabolized through multiple enzymes
including CYP3A4, CYP2C19, CYP2D6, and others to metabolites which appear to be more
active than the parent compound.130 The active metabolites 4-hydroxytamoxifen (4OH-TAM)
and 4-hydroxy-N-desmethyltamoxifen (endoxifen) have nearly a 100-fold higher affinity for the
estrogen receptor compared to tamoxifen. Endoxifen is present in the serum at a 6- to 12-fold
higher concentration compared to 4OH-TAM, hence endoxifen is thought to be the most
important metabolite for the clinical activity of tamoxifen. The formation of endoxifen is highly
dependent on the enzymatic activity of CYP2D6. However, multiple other pathways may also be
important for determining activity, including deactivation pathways (e.g., SULT-1-A1, UGT).
Polymorphisms in CYP2D6 can lead to increased or decreased formation of endoxifen and may
be related to improved or diminished clinical outcomes, respectively. Although there are clinical
data to suggest that certain polymorphisms in CYP2D6 may result in poorer disease-free or
relapse-free survival in patients receiving tamoxifen, these analyses are based mostly on
retrospective analyses and contradictory studies also exist to refute these claims. Multiple
commercially available assays for CYP2D6 are available, but widespread testing for patients
receiving tamoxifen is not currently recommended based on available evidence.47,88 Excellent
reviews on this subject are available.130 Potent inhibitors of CYP2D6, such as paroxetine and
fluoxetine, may decrease levels of endoxifen in patients receiving tamoxifen.131 The clinical
outcomes related to such drug-drug interactions in an individual patient are largely unknown and
depend on their underlying CYP2D6 genetic status (e.g., poor metabolizer, extensive
metabolizer). However, common sense would dictate avoiding known strong inhibitors of
CYP2D6, if possible, in patients receiving tamoxifen.
Figure 136-6.
Tamoxifen metabolism.131 Widths of the arrows approximate allocation of parent compound to

various metabolites. See text for further explanation.
The most reliable information regarding the side effects of tamoxifen comes from the NSABP
Breast Cancer Prevention Trial (P1).55 This trial randomized 13,388 women 35 years of age or
older who were at increased risk for breast cancer to placebo (n = 6,707) or to 20 mg/day of
tamoxifen (n = 6,681) for 5 years. Although the primary finding of this study is that tamoxifen
reduces the risk of invasive breast cancer by 49%, this study also provides an excellent
opportunity to determine the risk of side effects associated with tamoxifen. Information was
prospectively collected with regard to the occurrence of hot flashes, vaginal discharge, irregular
menses, fluid retention, nausea, skin changes, diarrhea, and weight gain or loss. The self-
administered depression scale and a global quality-of-life and a sexual function scale were
administered at each follow-up visit. The only symptomatic differences noted between the
placebo and tamoxifen group were related to hot flashes and vaginal discharge, both of which
occurred more often in the tamoxifen group. No important differences between the two groups
were observed in the various self-reporting instruments. Tamoxifen did not increase the risk of
ischemic heart disease, but reduced the risk of hip radius and spine fractures. Of note, the rates of
stroke, pulmonary embolism, and deep vein thrombosis were elevated in the tamoxifen group
(stroke: RR, 1.59; pulmonary embolism: RR, 3.01; and deep vein thrombosis: RR, 1.60),
particularly in women age 50 years or older. The rate of endometrial cancer was increased in the
tamoxifen group (RR, 2.53), and this increased risk occurred predominantly in women age 50
years or older. The increased risk of endometrial carcinoma is similar in magnitude to that
associated with postmenopausal estrogen replacement therapy and is likely a consequence of an
estrogenic effect of tamoxifen on the endometrium. Some experts argue that this risk is
acceptable because the endometrial cancer induced by tamoxifen is low stage, low grade, and
easily treated with surgery or other means and does not pose a life-threatening risk to women.
Tamoxifen was also associated with an increased risk of uterine sarcomas (a more aggressive
form of endometrial cancer), but this risk appears to be lower than the more common
endometrial cancers identified in the NSABP P-1 study.132 Routine endometrial biopsy is not
currently recommended for women receiving tamoxifen therapy. However, women receiving
tamoxifen therapy should be counseled to have regular gynecologic examinations and
immediately report unusual vaginal bleeding to their primary clinicians for further evaluation.
Toremifene is another marketed antiestrogen whose primary advantage is a lower estrogenic-to-

antiestrogenic ratio as compared to tamoxifen (based on laboratory data).133 Toremifene (60 mg
orally daily) has been found to have efficacy similar to that of tamoxifen in metastatic disease
and a generally similar side-effect profile.134 Toremifene is currently indicated as an alternative
to tamoxifen in patients with metastatic breast cancer, but studies are ongoing to evaluate its
safety and efficacy in the adjuvant setting. Preliminary results from these trials indicate similar
efficacy and safety, with possibly inferior bone protection with toremifene.135,136 However,
further follow-up is required to determine the long-term effects of toremifene in the adjuvant
setting.
In premenopausal women, the use of LHRH-agonists or other means of ovarian ablation provides
benefit in the adjuvant setting. In the EBCTCG overview analysis published in 2005, the overall
benefit of ovarian ablation or suppression was significant compared with no treatment, but
smaller than previously reported in 1996 (reduction in annual odds of recurrence = 25% ± 12%
in women <40 years old and 29% ± 6% in women 40–49 years old).5 Many of the ongoing trials
with the LHRH agonists were not yet included in this analysis and most of the clinical trials
analyzed included patients with hormone receptor-positive, -negative, and unknown status. In an
update of this analysis, study inclusion was restricted to patients treated with ovarian suppression
with LHRH agonists (not ovarian oblation or oophorectomy) and those patients with tumors
known to be hormone receptor-positive.137 The addition of a LHRH agonist reduced the rates of
recurrence by 25%, deaths after recurrence by 28%, and all deaths by 27% in women younger
than 40 years; no significant reductions in recurrence or death were noted in patient older than 40
years. Also, a similar benefit was observed with goserelin as compared with CMF chemotherapy
in hormone-sensitive premenopausal breast cancer patients, but not in patients with hormone
receptor-negative tumors.137 It is not clear whether the benefit of chemotherapy in this population
is a result of the actual effects of chemotherapy or a result of the endocrine effects of
chemotherapy-induced menopause. Consequently, some studies have investigated the benefits of
adding ovarian ablation or suppression to chemotherapy, either with or without tamoxifen.
Results from these studies clearly indicate a benefit from ceasing menses, regardless of whether
this is caused by chemotherapy or ovarian ablation or suppression.137 It is not clear whether the
addition of an LHRH agonist to tamoxifen is advantageous in women with hormone receptor-
positive tumors who continue to menstruate after chemotherapy. The optimal duration of
adjuvant LHRH agonist use is unknown, with trials ranging from 18 months to 5 years of
treatment. Multiple ongoing trials are attempting to answer this question; these trials include an
LHRH agonist alone, with tamoxifen or with an aromatase inhibitor. Currently, the only trial
with available results is a study by the Austrian Breast and Colorectal Cancer Study Group
(ABCSG-12) which randomized premenopausal patients with hormone receptor-positive early
stage breast cancer to 3 years of tamoxifen or anastrozole, both concomitantly with goserelin for
ovarian suppression.138 After a median follow-up of 48 months, there was no significant
difference in DFS between the two groups. However, a tamoxifen-only arm was not included in
this trial.
In postmenopausal women, aromatase inhibitors (AI) are gradually replacing tamoxifen in the
adjuvant setting. Four different approaches to therapy have been undertaken with these new
agents: (a) direct comparison with tamoxifen for adjuvant hormonal therapy, (b) sequential use
after 5 years of adjuvant tamoxifen therapy, (c) sequential use after 2 to 3 years of adjuvant
tamoxifen, and (d) 2 years of treatment with an AI followed by 3 years of adjuvant tamoxifen.
Anastrozole and letrozole have been directly compared with tamoxifen as initial therapy in
postmenopausal women with hormone receptor-positive, early stage breast cancer (ATAC
[Arimidex, Tamoxifen, Alone or in Combination] Trial and BIG [Breast International Group] 1–
98 Trial).139,140 These comparisons show an advantage with the aromatase inhibitors over
tamoxifen in terms of DFS. Other approaches to adjuvant hormonal therapy with AIs include
sequential use of newer agents after either 5 years or 2 to 3 years of tamoxifen. In the MA-17
study, 5 additional years of letrozole was compared with placebo in postmenopausal breast
cancer patients who had completed 5 years of tamoxifen therapy.141 After a median follow-up of
2.4 years, letrozole was associated with superior estimated 4-year DFS as compared with placebo
(93% vs 87%; P <0.001). Because of this difference, patients were unblinded and allowed to
crossover to the active arm of therapy. In a pooled analysis of trials investigating a switch to an
AI, 9,015 patients who had completed 2 to 3 years of adjuvant tamoxifen therapy were
randomized to continue tamoxifen or crossover to anastrozole or exemestane for the remainder
of 5 years.142 The results of this analysis show a decreased risk of recurrence at 6 years following
randomization in patients who switched to an AI as compared to those who continued with
tamoxifen alone (12.6% vs 16.0%; P <0.00001). The BIG 1–98 trial which compared letrozole
with tamoxifen also included two separate arms which investigated the value of switching from
tamoxifen to an AI or vice versa. With 71 months of follow-up, the sequential arms did not
improve estimated 5-year DFS compared to letrozole alone in either comparison.143 Clinical
trials are also investigating longer durations of AI use to assess the benefits and harms of
continued estrogen deprivation, the results of which are greatly anticipated.
Most national and international guidelines currently recommend incorporation of an AI into the
adjuvant hormonal therapy regimen for all postmenopausal, hormone-sensitive breast cancers.47
The current NCCN guidelines for breast cancer management state that any of the following are
acceptable endocrine therapy regimens for these women: (a) an AI for 5 years (or longer, based
on expert opinion); (b) tamoxifen for 2 to 3 years followed by an AI for a total of 5 years of
endocrine therapy; or (c) tamoxifen for 5 years followed by an AI for another 5 years (total of 10
years of endocrine therapy).47 The NCCN panel believes that the three available AIs
(anastrozole, letrozole, and exemestane) have similar antitumor efficacy and toxicity profiles and
many other clinicians agree. Therefore, the optimal hormonal therapy regimen in the adjuvant
setting has yet to be determined, and results from ongoing trials are eagerly awaited to more
clearly define a treatment strategy for women facing this clinical dilemma.
AIs are generally well tolerated. Adverse effects include bone loss/osteoporosis, hot flashes,
myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea. Although concerns
surrounding loss of bone density and an increased risk of osteoporosis are evident in these
adjuvant trials, the overall impact on quality-of-life and long-term survival are still being
evaluated. Bisphosphonates are coadministered with the AI in many patients in the metastatic
setting and may also be beneficial in the adjuvant setting. Other adverse events that are
worrisome include questionable effects on the cardiovascular system (e.g.,
hypercholesterolemia), cognitive functioning and joint health. Longer follow-up from these trials
will continue to provide valuable information to guide treatment decisions and side-effect
management.
Sidebar: Clinical Controversy
The optimal use of antiaromatase agents in the adjuvant setting for postmenopausal women
with hormone receptor-positive tumors is controversial. Multiple studies have been published
with results indicating a benefit to regimens that include an aromatase inhibitor as initial
therapy or after tamoxifen. However, many questions remain as to the optimal drug, dose,
sequence, and duration of therapy for these agents.
In summary, tamoxifen has been used in the adjuvant setting for nearly 30 years and has a
very well-defined safety and efficacy profile in this setting. Although it is difficult to define
the role of new therapies given the lengthy history of tamoxifen, the role of tamoxifen in the
adjuvant setting is changing with the incorporation of newer agents either concurrently (e.g.,
LHRH agonists) or sequentially (e.g., AIs).
Tamoxifen
Tamoxifen (Systemic)
Introductory Information
A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.128
Class: 10:00 Antineoplastic Agents; an500 (VA primary)
Brands*: Nolvadex®
*
also available generically
Generic Name: Tamoxifen Citrate
CAS Number: 54965-24-1
Chemical Name: 2-Hydroxy-1,2,3-propanetricarboxylate-(Z)-2-[4-(1,2-diphyl-1-
butenyl)phenoxy]-N,Ndimethyl ethanamine
Molecular Formula: C26H29NO•C6H8O7
Investigational Drug Number: ICI 46,474
Boxed Warning
• For women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer:
serious and life-threatening events associated with tamoxifen in the risk reduction setting include
uterine malignancies, stroke, and pulmonary embolism.a Incidence rates for these events have
been estimated from the NSABP P-1 trial (median length of follow-up 6.9 years).a
Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1000 women-
years of 2.2 for tamoxifen versus 0.71 for placebo) and uterine sarcoma (incidence rate per 1000
women-years of 0.17 for tamoxifen versus 0 for placebo).
For stroke, the incidence rate per 1000 women-years was 1.43 for tamoxifen versus 1 for placebo.a
For pulmonary embolism, the incidence rate per 1000 women-years was 0.75 for tamoxifen versus
0.25 for placebo.a
• Health care providers should discuss the potential benefits versus the potential risks of these
serious events with women at high risk of breast cancer and women with DCIS considering
tamoxifen to reduce their risk of developing breast cancer.a
• The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.a
Uses
Breast Cancer
An adjuvant to surgery and radiation therapy for the treatment of breast cancer in women with
negative axillary lymph nodes and in postmenopausal women with positive axillary lymph
nodes.110, 121, 128, 130, 133, 136, 194, 195, 196, 198, 204, 205, 253, 254, 258 Also reduces the occurrence of
contralateral breast cancer in these women.128, 253, 254, 258
Reduction of risk of invasive breast cancer in patients with DCIS following surgery and radiation
therapy.a
Palliative treatment of metastatic breast cancer in men and women.128 An alternative to ovarian
ablative therapy (oopherectomy or radiation) in premenopausal women.128, 133, 158, 159, 160, 161, 162,
163, 164, 165, 166, 167, 168, 169, 183
Reduction in the incidence of breast cancer in women at high risk for developing the disease.128,
293
Albright's Syndrome
Has been used to reduce the frequency of vaginal bleeding episodes and to reduce the rate of
increase in bone age in girls with Albright's syndrome (McCune-Albright syndrome ) and
precocious puberty.a
Long-term effects not established.a
Dosage and Administration
General
• Consult specialized references for procedures for proper handling and disposal of antineoplastic
drugs.
Administration
Administered orally as a single daily dose or in divided doses; dosages exceeding 20 mg daily
should be given in divided doses (morning and evening).128
Initiate therapy during menstruation when used to reduce the incidence of breast cancer in
sexually active women.a In women with menstrual irregularity, a negative β-human chorionic
gonadotropin test immediately prior to therapy is sufficient.a
Dosage
Available as tamoxifen citrate; dosage expressed in terms of tamoxifen.128
Adults
Breast Cancer
>Adjuvant Therapy
Oral: 20-40 mg daily.100, 102, 110, 121, 128, 129, 130, 194, 195, 196, 205 Current data from clinical studies
support 5 years of adjuvant therapy.128, 194, 195, 196, 253, 254, 256, 257, 291, 328
>Ductal Carcinoma in Situ

Oral: 20 mg daily for 5 years.a
>Metastatic Breast Cancer

Oral: 20-40 mg daily.128
>Reduction in the Incidence of Breast Cancer in Women at High Risk

Oral: 20 mg daily for 5 years.128, 270, 284, 291
Prescribing Limits
Adults
Breast Cancer
>Adjuvant Therapy
Oral: No evidence that dosages >20 mg daily are more effective.112, 128
Cautions
Contraindications
• Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

• When used in women with DCIS and women at high risk for breast cancer, history of DVT or
pulmonary embolism.a
• When used in women with DCIS and women at high risk for breast cancer, concurrent
anticoagulant therapy with a warfarin derivative.a, 278, 293, 309
Warnings/Precautions
Warnings
Hypercalcemia
Hypercalcemia reported in patients with metastatic breast cancer who have bone metastases.128,
129
If hypercalcemia occurs, take appropriate measures; if severe, discontinue tamoxifen.128
Effects on the Uterus

Increased incidence of uterine malignancies, sometimes fatal, reported.128, 330 Most uterine
malignancies have been classified as adenocarcinoma of the endometrium; rare uterine sarcomas
also reported.128, 330 (See Boxed Warning.) Gynecologic symptoms (i.e., menstrual irregularities,
abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be
promptly evaluated.128, 163, 183
Endometrial changes, including hyperplasias and polyps, endometriosis and uterine fibroids
reported.128, 180, 258, 259, 274 Ovarian cysts reported in a small number of premenopausal women
with advanced breast cancer.128
Cardiovascular Effects
Increased incidence of thromboembolic events, including DVT128, 293 and pulmonary embolism;
269, 270, 293
stroke also reported.128, 269, 277, 293 Some cases of stroke and pulmonary emboli have
been fatal.128 (See Boxed Warning.) Concomitant use with chemotherapy may increase incidence
of these events.128
Hepatic Effects
Liver cancer reported.128
Changes in AST, ALT, bilirubin and/or alkaline phosphatase concentrations reported; severe
hepatic abnormalities including fatty changes in the liver, cholestasis, hepatitis, and hepatic
necrosis (some fatal) reported rarely.128
Ocular Effects
Visual disturbances, decrement in color vision perception, corneal changes, cataracts, optic
neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or
retinopathy reported.128, 190, 191, 192, 193, 258, 268, 326
Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.128 If inadvertently used during pregnancy or if patient becomes pregnant,
apprise of potential fetal hazard, including possible long-term risk of a diethylstilbestrol-like
syndrome.128
General Precautions
Hematologic Effects
Thrombocytopenia, neutropenia, pancytopenia, and leukopenia reported; caution in patients with
leukopenia or thrombocytopenia.128 Periodic CBCs, including platelet count recommended.128
Specific Populations
Pregnancy
Category D.128 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Not known whether tamoxifen is distributed into milk.128 Discontinue nursing or the drug
because of potential risk to nursing infant.128
Pediatric Use
Safety and efficacy in girls 2-10 years of age with Albright's syndrome and precocious puberty
not studied beyond 1 year; long-term effects not established and continued monitoring
recommended.a (See Special Populations under Pharmacokinetics.)
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults.a
Common Adverse Effects
Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128
Interactions
A substrate of CYP3A, 2C9, 2D6.a
Effect of tamoxifen on drugs that require mixed function oxidases for activation unknown.a
Cytotoxic Agents
Increased risk of thromboembolic events.128
Specific Drugs
Drug Interaction Comments

Decreased plasma tamoxifen and N-
Aminoglutethimide
desmethyltamoxifen concentrations128
Careful monitoring of PT is
Anticoagulants (e.g., Enhanced warfarin effects128, 170, 171,
172 recommended128, 170, 171, 172
warfarin)
When used in women with DCIS
or at high risk for breast cancer,
concomitant use contraindicateda
Increased plasma tamoxifen and N-
Bromocriptine
desmethyltamoxifen concentrations128
Competitively inhibited formation of
Cyclosporine Clinicial importance unknowna
N-desmethyltamoxifen in vitroa
Diltiazem Clinicial importance unknowna
Erythromycin Clinicial importance unknowna
Decreased plasma letrozole
Letrozole
concentrationsa
Decreased plasma N-
desmethyltamoxifen concentrations
Medroxyprogesterone
but did not reduce plasma tamoxifen
concentrationsa
Nifedipine Clinicial importance unknowna
Decreased plasma tamoxifen
Phenobarbital Clinical importance unknown128
concentrations128
Decreased plasma tamoxifen and N-
Rifampin
desmethyltamoxifen concentrationsa
Pharmacokinetics
Absorption
Bioavailability
Absorbed slowly following oral administration; peak serum concentrations of tamoxifen occur
about 3-6 hours after a single dose.128, 137, 138, 139, 140, 141
Plasma Concentrations
Steady-state concentrations of tamoxifen are attained after 3-4 weeks and those of N-
desmethyltamoxifen, an active metabolite, are attained after 3-8 weeks.128, 137, 140, 143, 145
Distribution
Extent
Not fully characterized.128
Not known whether tamoxifen is distributed into milk.128
Elimination
Metabolism
Rapidly and extensively metabolized.26, 28, 140, 142, 143, 144, 145, 146, 148, 149, 150, 151 The major
metabolite, N-desmethyltamoxifen,128, 140, 143, 144, 145, 146, 148, 150, 151 has biologic activity similar to
that of the parent drug.128
Elimination Route
Excreted principally in feces as polar conjugates.128
Half-life
Tamoxifen: 5-7 days.28, 137, 139, 145
N-Desmethyltamoxifen: 9-14 days.128, 139, 145
Special Populations
Clearance higher in female children 2-10 years of age than in women; exposure to N-
desmethyltamoxifen in these pediatric patients similar to adults.a
Stability
Storage
Oral
Tablets
Well-closed, light-resistant containers 20-25°C.128
Actions
• Acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on
endometrium, bone, and lipids.311
• In breast epithelial tissue, increases production of inhibitory factors and decreases production of
stimulatory factors that influence breast cell growth.271, 286, 287, 323
• Reduces bone resorption and bone turnover.265, 266, 267, 316
• Decreases total and LDL-cholesterol concentrations.318, 319, 320 Less favorably, decreases HDL-
cholesterol concentrations and increases triglyceride concentrations.318, 319, 320
• Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects
on the endometrium.311
Advice to Patients
• Importance of receiving routine gynecologic care and of immediately informing clinician if any
new breast lumps or abnormal gynecologic symptoms, including abnormal vaginal bleeding,
change in vaginal discharge, menstrual irregularities, or pelvic pain/pressure occur.128, 163, 183
• Importance of informing clinician of any changes in vision.128, 190, 191, 192, 193, 258, 268
• Importance of immediately informing clinician of unexplained shortness of breath or leg
swelling/tenderness.128
• Importance of periodic monitoring, including liver function test monitoring and blood counts.128
• Advise patients at high risk of breast cancer that tamoxifen may decrease the incidence of breast
cancer, but may not eliminate the risk of the disease.128
• Importance of women informing clinicians immediately if they are or plan to become pregnant;
importance of avoiding pregnancy during therapy;119, 128, 243 importance of using effective
nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the
drug.a Necessity of advising pregnant patients of the risk to the fetus.128
• Importance of reading the medication guide; the guide is for women using tamoxifen to lower
their risk of breast cancer or with DCIS.128
• Importance of informing clinicians of existing or contemplated concomitant therapy, including
prescription and OTC drugs.128
• Importance of women informing clinicians if they are or plan to breast-feed.128
• Importance of informing patients of other important precautionary information.128 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in
some individuals; consult specific product labeling for details.
Tamoxifen Citrate
Dosage
Routes Strengths Brand Names Manufacturer
Forms
10 mg (of
Oral Tablets Nolvadex® AstraZeneca
tamoxifen)*
Tamoxifen Citrate Aegis, Andrx, Barr, Mylan,
Tablets Roxane, Teva
20 mg (of
Nolvadex® AstraZeneca
tamoxifen)*
Tamoxifen Citrate Aegis, Andrx, Barr, Mylan,
Tablets Roxane, Teva
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing
information was updated 03/2011. For the most current and up-to-date pricing information,
please visit www.drugstore.com. Actual costs to patients will vary depending on the use of
specific retail or mail-order locations and health insurance copays.
Nolvadex 20MG Tablets (ASTRAZENECA): 30/$120.99 or 60/$239.98
Tamoxifen Citrate 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$21.99 or

90/$49.97
Use is not currently included in the labeling approved by the US Food and Drug
Administration.
Anastrazole
Anastrozole (Systemic)
Antineoplastic agent; selective aromatase inhibitor (type II).1, 16, b
Brands: Arimidex®
Generic Name: Anastrozole

CAS Number: 120511-73-1
Chemical Name: α,α,α´,α´-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile
Molecular Formula: C17H19N5
Uses
Breast Cancer
First-line therapy for hormone receptor-positive (i.e., estrogen receptor-positive, progesterone

receptor-positive, or both) or hormone receptor-unknown locally advanced or metastatic breast
cancer in postmenopausal women.1, 15, 20, b
Second-line therapy for advanced breast cancer in postmenopausal women with disease
progression following tamoxifen therapy.1, 20, b Usually ineffective in patients with hormone-
receptor-negative breast cancer and those who fail tamoxifen therapy.1, b
Adjunct to surgery (with or without radiation therapy and/or chemotherapy) either as treatment
of choice or as an alternative agent in postmenopausal women for early-stage hormone receptor-
positive breast cancer.1, 15, 20, 49, b May be more effective than tamoxifen;24, 50 however, further
studies needed to clarify efficacy and safety.25
A treatment of choice as initial adjuvant therapy for postmenopausal women with hormone
receptor-positive invasive breast cancer who have a contraindication to tamoxifen.49 Alternative
agent in postmenopausal women at increased risk for tamoxifen-associated toxicity (e.g., those
with a history of thromboembolic or cerebrovascular disease).25, 29
Not recommended as a single agent in premenopausal women with breast cancer.1, 25, 48, 49, b (See
Contraindications under Cautions.)
Not recommended as adjuvant therapy in postmenopausal women with hormone-receptor-

negative breast cancer.1, 25, 49, b
Has been used as sequential adjuvant therapy following adjuvant tamoxifen for hormone
receptor-positive early-stage breast cancer in postmenopausal women.20, 49
Has been used as extended adjuvant therapy following adjuvant tamoxifen for hormone receptor-
positive early-stage breast cancer in postmenopausal women.54
Has been used for reduction in the incidence of breast cancer in women at high risk for
developing the disease.44
Has been used as adjuvant therapy in premenopausal women with hormone receptor-positive
breast cancer in combination with a luteinizing hormone-releasing hormone (LHRH)

agonist (e.g., goserelin).25, 49
Gynecomastia
Has been used in adolescent boys for treatment of pubertal gynecomastia ; however,
manufacturer states that efficacy is not established.b
McCune-Albright Syndrome
Has been used in young girls with McCune-Albright syndrome and progressive precocious
puberty ; however, manufacturer states that efficacy is not established.b
General
• Consult specialized references for procedures for proper handling and disposal of antineoplastic
drugs.
• Administration of corticosteroid replacement therapy not necessary.1, b (See Actions.)
Administration
Oral Administration
Administer orally once daily without regard to meals.1, b
Dosage
Adults
Breast Cancer
>First-line Treatment of Locally Advanced or Metastatic Breast Cancer
Oral: 1 mg once daily.1, b Continue therapy until tumor progresses.1, b
>Second-line Treatment of Advanced Breast Cancer
Oral: 1 mg once daily.1, b Continue therapy until tumor progresses.1, b
>Adjuvant Treatment of Early Breast Cancer

Oral: 1 mg once daily.1, b Optimum duration unknown; duration of therapy in clinical study was
5 years.1, b
Special Populations
Hepatic Impairment
Dosage adjustment not required in patients with mild to moderate hepatic impairment.1, b (See
Special Populations under Pharmacokinetics.)
Not studied in patients with severe hepatic impairment.1, b
Renal Impairment
Dosage adjustment not required.1, b (See Special Populations under Pharmacokinetics.)
Geriatric Patients
Dosage adjustment not required.1, b (See Special Populations under Pharmacokinetics.)
Cautions
Contraindications
• Known hypersensitivity to anastrozole or any ingredient in the formulation.1, b

• Premenopausal women.b
• Pregnancy.b
Warnings
Increased incidence of ischemic cardiovascular events (e.g., angina pectoris) reported in patients
with preexisting ischemic heart disease; consider risks and benefits of therapy in these patients.b
Musculoskeletal Effects
Risk of osteoporosis;36, c decreases in bone mineral density (BMD) at lumbar spine and hip
reported.43, 48, b
Risk of adverse musculoskeletal effects (e.g., joint disorder, arthritis, arthrosis, arthralgia) and
fractures (including fractures of the spine, hip, and wrist).1, b
Monitor BMD prior to and at annual intervals during therapy.36, 37, c
Therapy with an oral bisphosphonate agent recommended in patients with osteoporosis; carefully
monitor patients with osteopenia.36, 46, 47
Lipid Effects
Increases in total serum cholesterol reported during therapy;b consider monitoring serum
cholesterol.46, b

May cause fetal harm; embryotoxic and fetotoxic in animals.1, b Exclude pregnancy before
initiating treatment.1 If used during pregnancy or patient becomes pregnant, apprise of potential
fetal hazard.1, b (See Contraindications under Cautions.)
Sensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis, angioedema and urticaria reported
rarely.1, 48, b Possible mucocutaneous disorders (e.g., erythema multiforme and Stevens-Johnson
syndrome).1, b
General Precautions
Hepatic Effects
Increases in serum AST, ALT, and alkaline phosphatase concentrations reported commonly;1, b
hepatitis and increased serum concentrations of γ-glutamyltransferase (GGT) and bilirubin
reported rarely.1, b
Pregnancy
Category X.b (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under
Cautions.)
Lactation
Not known whether anastrozole is distributed into milk; discontinue nursing or the drug.b
Pediatric Use
Safety and efficacy not established.1, 47
Has been used in clinical studies of adolescent boys 11-18 years of age with gynecomastia
and in girls 2 to <10 years of age with McCune-Albright syndrome and progressive precocious
puberty ;b however, efficacy not established for these indications.b
Geriatric Use
No substantial differences in efficacy for patients ≥65 years of age relative to younger adults
when used as second line therapy for advanced breast cancer;1, b moderately greater efficacy
observed for patients ≥65 years of age when used as first-line therapy for locally advanced or
metastatic breast cancer.1, b
For adjuvant treatment of hormone receptor-positive early-stage breast cancer, efficacy (e.g.,
disease-free survival benefit) in postmenopausal women ≥65 years of age was less than efficacy
observed in postmenopausal women <65 years of age.b
Hepatic Impairment
Not studied in patients with severe hepatic impairment.1, b
Vasodilation, hot flushes (flashes), diarrhea, nausea, vomiting, asthenia, pain (including back
pain), arthritis, arthralgia, fractures, increased liver function tests, hypertension, osteoporosis,
peripheral edema, lymphedema, pharyngitis, depression, rash, insomnia, headache, increased
cough, dyspnea.b
Interactions
Inhibits CYP1A2, 2C8/9, and 3A4 in vitro, but only at relatively high concentrations.1, b Does
not inhibit CYP2A6 or CYP2D6 in vitro.1, b Pharmacokinetic interaction unlikely with drugs
metabolized by CYP isoenzymes at recommended dosages.1, b
Specific Drugs
Drug Interaction Comment

Pharmacokinetic interaction
Antipyrine
unlikely1, b
Antagonistic pharmacologic
Estrogens Concomitant use not recommended1, b
effects1, b
Concomitant use not recommended36, 37
Advise women receiving anastrozole who require
Possible decreased plasma
Raloxifene osteoporosis therapy that an oral bisphosphonate
anastrozole concentrations36, 37
(rather than raloxifene) is recommended36, 37, 46,
47
Possible decreased plasma

Tamoxifen Concomitant use not recommended1, 36, 37, b
anastrozole concentrations1, 26, b
No clinically important effects on
Warfarin anticoagulant activity or
pharmacokinetics of warfarinb
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed after oral administration, with peak plasma concentrations usually attained
within 2 hours under fasting conditions.b
Steady-state plasma concentrations achieved in about 7 days.1, b
Onset
Serum estradiol concentrations reduced by approximately 70% within 24 hours of a 1-mg dose1, b
and by approximately 80% after 14 days of daily dosing.1, b
Duration
Suppression of serum estradiol concentrations maintained for up to 6 days after discontinuance
of daily anastrozole administration.1, b
Food
Food reduces rate but does not affect extent of absorption.1, b
Distribution
Extent
Anastrozole crosses the placenta in animals;1, b not known whether anastrozole crosses the
placenta in humans.1
Not known whether anastrozole is distributed into milk.1, b
Plasma Protein Binding

40%.1, b
Elimination
Metabolism
Undergoes N-dealkylation, hydroxylation, and glucuronidation in the liver to multiple,
pharmacologically inactive, metabolites.1, b
Elimination Route
Hepatic metabolism (85%) and renal excretion (10%).b
Half-life
Terminal half-life is approximately 50 hours in postmenopausal women.1, b
Special Populations
No evidence of altered pharmacokinetics observed in women >80 years of age compared with
women <50 years of age.1, b
Individuals with severe renal impairment (Clcr <30 mL/minute): Renal clearance and total body
clearance decreased by approximately 50 and 10%, respectively.b
Individuals with stable hepatic cirrhosis (related to alcohol abuse): Clearance reduced by
approximately 30% compared with those with normal hepatic function;1 however, plasma
concentrations within range compared with individuals with normal hepatic function.1, b
Stability
Storage
Oral
Tablets
20-25°C.1, b
Actions
• Selectively inhibits conversion of androgens to estrogens.1, 6, 14

• Decreased serum and tumor concentrations of estrogen inhibit breast tumor growth and delay
disease progression.1, 14, 16
• Does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.1, 6, 14, b
Advice to Patients
• Importance of providing patient with a copy of the manufacturer's patient information.c

• Advise patients that anastrozole may be administered without regard to meals.1, b, c
• Risk of osteoporosis.c Life-style changes (e.g., weight-bearing exercise, abstinence from smoking,
moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D
advised.36, 46, 47
• Advise patients that anastrozole is for use in postmenopausal women only.1, 47
• Importance of women informing their clinician if they are or plan to become pregnant or plan to
breast-feed; importance of avoiding pregnancy during therapy.1 Warn women of potential hazard
to the fetus in cases of inadvertent exposure of pregnant women to anastrozole.b
prescription (e.g., estrogens, raloxifene, tamoxifen), OTC, and herbal drugs, as well as
concomitant illnesses (e.g., ischemic heart disease).1, b, c
Preparations
Anastrozole
Routes Dosage Forms Strengths Brand Names Manufacturer
Oral Tablets, film-coated 1 mg Arimidex® AstraZeneca
Comparative Pricing
Arimidex 1MG Tablets (ASTRAZENECA): 30/$455.01 or 90/$1308.9
Administration.
Toremifen
Toremifene (Systemic)
Antineoplastic agent; a nonsteroidal estrogen agonist-antagonist that is structurally and

pharmacologically related to tamoxifen.1, 3, 19, 20
Brands: Fareston®
Generic Name: Toremifene Citrate

Chemical Name: 2-Hydroxy-1,2,3-propanetricarboxylate (1:1) (Z)-2-[4-(4-chloro-1,2-diphenyl-1-
butenyl)phenoxy]-N,N-dimethylethanamine
Molecular Formula: C26H28ClNO•C6H8O7
Investigational Drug Number: CCRIS 6719, FC 1157a, NK 622
Uses
Breast Cancer
Palliative treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor

positive or estrogen-receptor unknown tumors1, 4, 11, 15, 21 (designated an orphan drug by FDA for
this use).17 Not recommended for treatment of estrogen-receptor negative breast tumors.5, 7
Similar efficacy and toxicity as tamoxifen.1, 3, 4, 11, 15, 26 Not known whether toremifene offers a
therapeutic advantage over tamoxifen for the treatment of advanced breast cancer in eligible
patients.18, 19, 27
Under investigation for use as adjuvant therapy for early-stage breast cancer in node-
positive postmenopausal women.31, 32 Results from trials to date suggest similar efficacy and
toxicity as tamoxifen.31, 32
Efficacy in treatment of advanced breast cancer in men not demonstrated.29, 30
Because of demonstrated cross-resistance with tamoxifen, usefulness of toremifene as second-
line endocrine therapy for treatment of metastatic breast cancer refractory to tamoxifen
appears to be limited.3, 13, 14, 19
Prostate Cancer
Under investigation as a preventive agent for prostate cancer in men with high-grade
prostatic intraepithelial neoplasia and no evidence of prostate cancer.33
Administration
Oral Administration
Administer orally without regard to meals.1
Dosage
Available as toremifene citrate; dosage expressed in terms of toremifene.1
Adults
Breast Cancer
Oral: 60 mg once daily for metastatic breast cancer.1 Continue therapy until disease progression
occurs; in clinical studies, therapy was continued for a median duration of 5 months.1
Prescribing Limits
Adults
Breast Cancer
Oral: Higher dosages (200 or 240 mg daily) associated with greater toxicity but provide no
additional benefit in metastatic breast cancer.1, 11, 15
Special Populations
Hepatic Impairment
Use with caution and monitor liver function carefully.10 Dosage reduction may be necessary.10
Renal Impairment
Dosage adjustments not required.10
Geriatric Patients
Dosage adjustments not required.9
Cautions
Contraindications
• Known hypersensitivity to toremifene or any ingredient in the formulation.1
Warnings
Hypercalcemia and Tumor Flare
Hypercalcemia and tumor flare reported (usually during the first weeks of therapy) in patients
with metastatic breast cancer who have bone metastases.1 Tumor flare is a syndrome of diffuse
musculoskeletal pain and erythema with increase and then regression in the size of tumor lesions;
tumor flare does not represent tumor progression or imply failure of treatment.1
Monitor patients with bone metastases closely for hypercalcemia during first weeks of therapy.1
If hypercalcemia occurs, institute appropriate measures; if severe, discontinue toremifene.1
Monitor serum calcium concentrations periodically during therapy.1
Effects on the Uterus

Endometrial hyperplasia and endometrial cancer reported.1, 30 Long-term therapy not
recommended in patients with preexisting endometrial hyperplasia.1, 30
Monitor carefully for uterine disorders.8, 29, 30 Gynecologic symptoms (i.e., menstrual
irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure)
should be promptly evaluated.1, 29 (See Advice to Patients.)

May cause fetal harm.1 Embryotoxicity and fetotoxicity demonstrated in animals.1 If used during
pregnancy or if patient becomes pregnant, apprise of potential fetal hazard and potential loss of
pregnancy.1
General Precautions
Pulmonary embolism, thrombophlebitis, thrombosis, cerebrovascular accident, and TIA
reported.1 Use not recommended in patients with history of thromboembolic disorders.1
Cardiac failure, MI, arrhythmia, angina pectoris, and edema reported.1
Hematologic Effects
Leukopenia and thrombocytopenia reported rarely;1 monitor leukocyte and platelet counts in
patients with leukopenia and thrombocytopenia.1
Monitor CBCs periodically during therapy.1
Hepatic Effects
Increased hepatic enzyme concentrations (e.g., AST, alkaline phosphatase, bilirubin) and
jaundice reported.1 Fatty liver and nonalcoholic steatohepatitis reported following long-term
therapy with higher than recommended dosage (i.e., 80 mg daily).25
Obtain liver function tests periodically during therapy.1
Ocular Effects
Cataracts, dry eyes, abnormal visual fields, corneal keratopathy, glaucoma, abnormal
vision/diplopia, and corneal opacity (corneal verticulata) reported.1 Blurred vision reported
following therapy with higher than recommended dosages (i.e., 200 or 240 mg daily).1
Pregnancy
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1, 30 Discontinue
nursing or the drug.30
Pediatric Use
Not labeled for use in children.1
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults,1 but increased
sensitivity cannot be ruled out.9
Hepatic Impairment
Decreased clearance in patients with hepatic impairment (i.e., cirrhosis, fibrosis).1, 10 (See
Elimination: Special Populations, under Pharmacokinetics.) Use with caution and monitor liver
function carefully.10 Dosage reduction may be necessary.10
Hot flushes (flashes), sweating, nausea, vaginal discharge, dizziness, edema, vomiting, vaginal
bleeding.1
Interactions
Metabolized principally by CYP3A4.1
No formal drug interaction studies to date.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4-6: Potential pharmacokinetic interaction (increased toremifene

concentrations).1, 29, 30 Clinical importance unknown.1
Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased toremifene

concentrations).1, 10, 24
Drugs Affecting Calcium
Drugs that decrease renal calcium excretion (e.g., thiazide diuretics): Potential pharmacologic
interaction (increased risk of hypercalcemia).1
Specific Drugs

Anticoagulants, oral (e.g., Possible increased PT1, 29, 30 Monitor PT; adjust
warfarin) anticoagulant dosage if
necessary1, 29, 30
Possible decreased toremifene
Anticonvulsants (e.g., Increase toremifene
concentrations (due to increased
carbamazepine, clonazepam, dosage if necessary1, 10,
clearance and decreased elimination half- 24
phenobarbital, phenytoin)
life of toremifene)1, 10, 24
Adjust toremifene
Antifungals, azoles (e.g., Possible increased toremifene
dosage if necessary1, 10,
ketoconazole) concentrations1, 29, 30 24
Adjust toremifene
Macrolides (e.g., Possible increased toremifene
dosage if necessary1, 10,
erythromycin) concentrations1, 29, 30 24
Increase toremifene
Decreased peak plasma concentration and
Rifampin dosage if necessary1, 10,
AUC of toremifene24 24
Pharmacokinetics
Absorption
Bioavailability
Well absorbed following oral administration, with peak plasma concentration usually attained
within 3 hours.1
Steady-state concentrations are reached in about 4-6 weeks.1
Food
Food does not appear to affect absorption.1
Distribution
Extent
Crosses the placenta and accumulates in the fetus in rodents.1 Distributed into milk in rats; not
known whether distributed into human milk.1

>99.5% (mainly albumin).1
Special Populations
Increased toremifene volume of distribution in geriatric female patients; however, no change in
AUC.1, 9
Elimination
Metabolism
Extensively metabolized, principally via CYP3A4 to N-demethyltoremifene, which exhibits
antiestrogenic effects but has weak antitumor potency in vivo.1
Elimination Route
Excreted as metabolites principally in feces, with about 10% excreted in urine over 1 week.1
Half-life
Toremifene: Approximately 5 days.1
N-demethyltoremifene: 6 days.1 Deaminohydroxy toremifene: 4 days.1
Elimination is slow due to enterohepatic circulation.1
Special Populations
Increased toremifene elimination half-life in patients with hepatic impairment (i.e., cirrhosis,
fibrosis).1, 10
Pharmacokinetics are not altered in patients with renal impairment.1, 10
Increased toremifene elimination half-life in geriatric female patients; however, no change in

clearance.1, 9
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15-30°C); protect from heat and light.1
Actions
• Acts as an estrogen antagonist on breast tissue and as a weak estrogen agonist on endometrium,
bone, and lipids.1, 3
• In breast cancer, competitively binds to estrogen receptors and blocks tumor growth stimulated by
estrogen.1, 3 Also may inhibit tumor growth through other mechanisms (e.g., induction of
apoptosis, regulation of oncogene expression and growth factors).3
• Decreases total and LDL-cholesterol concentrations.3, 6, 16
• Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects
on the endometrium.1
Advice to Patients
• Importance of receiving routine gynecologic care and of immediately informing clinician if any
new breast lumps or abnormal gynecologic symptoms, including menstrual irregularities,
abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure occur.1, 29
• Importance of informing patients with bone metastases about the typical manifestations of
hypercalcemia and instructing patients to report promptly any symptoms to their clinician.1
prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant
illnesses.1
breast-feed.1 Necessity for clinicians to advise women to avoid pregnancy during therapy and to
advise pregnant women of risk to the fetus and of potential loss of pregnancy.1
Preparations
Toremifene Citrate
®
Oral Tablets 60 mg (of toremifene) Fareston (with povidone) GTx
Comparative Pricing
Fareston 60MG Tablets (GTX): 30/$580.02 or 90/$1725.87
Administration.
Letrozole
Letrozole (Systemic)
Antineoplastic agent; selective aromatase inhibitor.1, 2, 3, 6, 11, 13, 15
Brands: Femara®
Generic Name: Letrozole

CAS Number: 112809-51-5
Chemical Name: 4,4´-(1H-1,2,4-triazol-1-ylmethylene)bis-benzonitrile
Molecular Formula: C17H11N5
Investigational Drug Number: CGS 20267
Uses
Breast Cancer
Adjuvant treatment in postmenopausal women with ER-positive early breast cancer.a, c Efficacy
based on analysis of disease-free survival in women treated with letrozole for a median of 24
months.a Follow-up analysis needed to determine long-term safety and efficacy.a
Extended adjuvant treatment in postmenopausal women with early-stage breast cancer who have
received 5 years of adjuvant tamoxifen therapy.a, 9, 25, 38 Efficacy based on analysis of disease-
free survival in women treated with letrozole for a median of 24 months.a Further data needed to
determine long-term outcome.a
First-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced

or metastatic breast cancer in postmenopausal women; superior to tamoxifen in producing
objective tumor response and delaying tumor progression.1, 9, 18, 20
Second-line therapy for advanced breast cancer in postmenopausal women with disease
progression following antiestrogen therapy (e.g., tamoxifen).1, 9, 10
Female Infertility
Has been used to induce ovulation in anovulatory women desiring pregnancy.d Letrozole is
not approved by FDA for this indication;e manufacturer states that the drug should not be given
to women who may become or are pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under
Cautions.)
General
• Administration of corticosteroid replacement therapy not necessary.1 (See Actions.)
Administration
Oral Administration
Administer orally once daily without regard to meals.1
Dosage
Adults
Breast Cancer
>Adjuvant Treatment of Early-stage Breast Cancer
Oral: 2.5 mg once daily.a Optimal duration unknown.a Planned duration of treatment in clinical
study was 5 years; median duration of treatment at time of analysis was 24 months; median
duration of follow-up was 26 months.a Discontinue if relapse occurs.a
>Extended Adjuvant Treatment of Early-stage Breast Cancer

Oral: 2.5 mg once daily.a Optimal duration unknown.a Planned duration of treatment in clinical
study was 5 years; median duration of treatment at time of analysis was 24 months; median
duration of follow-up was 28 months.a Discontinue if relapse occurs.a
>First-line Treatment of Locally Advanced or Metastatic Breast Cancer

Oral: 2.5 mg once daily.1 Continue therapy until tumor progresses.1
>Second-line Treatment of Advanced Breast Cancer

Oral: 2.5 mg once daily.1 Continue therapy until tumor progresses.1
Special Populations
Hepatic Impairment
Cirrhosis and severe hepatic impairment (Child-Pugh class C): Decrease dosage to 2.5 mg every
other day.1
Mild to moderate hepatic impairment: No dosage adjustment recommended.1
Renal Impairment
Clcr ≥10 mL/minute: No dosage adjustment necessary.1
Geriatric Patients
No dosage adjustment necessary.1
Cautions
Contraindications
• Known hypersensitivity to letrozole or any ingredient in the formulation.1
Warnings
May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 If inadvertently used
during pregnancy or patient becomes pregnant, apprise of fetal hazard and potential risk of
pregnancy loss.1
General Precautions
CNS Effects
Fatigue and dizziness reported; somnolence reported uncommonly.1 Caution advised when
driving or using machinery.1
Hepatic Effects
Abnormal liver function test results not associated with documented liver metastases reported in
women receiving second-line therapy.1
Lipid Effects
Increases in total serum cholesterol reported in women receiving adjuvant treatment.a
Effects on Bone
Risk of osteoporosis.a, 29 Use of letrozole in women receiving calcium and vitamin D who were
not receiving bisphosphonates has been associated with loss of bone mineral density (BMD) in
the hip and/or lumbar spine.a Consider monitoring BMD.29, 37, a
Pregnancy
Lactation
Not known whether letrozole is distributed into human milk; caution advised.1
Pediatric Use
Safety and efficacy not established in children of any age.1
Geriatric Use
No substantial differences in safety or efficacy relative to younger patients when used for
adjuvant therapy.a Possibility exists of greater sensitivity in some older individuals.a
In all studies of first- and second-line treatment, median patient age was 64-65 years; one-third
were ≥70 years of age.1 In the first-line clinical study, patients ≥70 years of age experienced
longer time to tumor progression and higher response rates than patients <70 years of age.1
Premenopausal Women
Not approved by FDA for use in premenopausal women.a, e
Hepatic Impairment
Dosage reduction recommended in patients with cirrhosis and severe hepatic impairment.1 Effect
of hepatic impairment on drug exposure in noncirrhotic cancer patients with increased bilirubin
concentrations not determined.1
Bone pain, hot flushes, back pain, nausea, arthralgia, dyspnea.1
Interactions
Metabolized by CYP3A4 and CYP2A6.1 Inhibits CYP2A6 and, to a lesser extent, CYP2C19 in
vitro.1
Specific Drugs

Antineoplastic No clinical experience with
agents concomitant use to date1
No clinically important effect on
Cimetidine
letrozole pharmacokinetics1
No substantial effect on letrozole or
Diazepam
diazepam metabolism in vitro1
Estrogens Antagonistic pharmacologic effectsb Concomitant use not recommendedb
Therapeutic effect of letrozole not
Decreased plasma letrozole
Tamoxifen impaired if used immediately after
concentrations1
tamoxifen1
No clinically important effects on
Warfarin
warfarin pharmacokinetics1
Pharmacokinetics
Absorption
Bioavailability
Rapidly and completely absorbed after oral administration.1
Onset
Plasma estradiol, estrone, and estrone sulfate reduced by 75-95% within 2-3 days with daily
dosages of 0.1-5 mg.1
Duration
Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.1
Food
Food does not affect absorption.1
Distribution
Extent
Not known if distributed into milk.1

Weakly bound.1
Elimination
Metabolism
Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.1
Elimination Route
Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about
9%), and unchanged drug (6%).1
Half-life
2 days.1
Special Populations
Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying
renal function.1 Renal impairment (Clcr 20-50 mL/minute) did not affect steady-state plasma
concentrations in patients with advanced breast cancer.1
AUC was increased twofold and clearance was decreased in adults with cirrhosis and severe
hepatic impairment (Child-Pugh class C); higher letrozole concentrations are expected in breast
cancer patients with severe hepatic impairment compared with patients with normal liver
function.1
AUC was increased (37%) in adults with moderate hepatic impairment (e.g., cirrhosis, Child-
Pugh class A and B); drug exposure was within range observed in patients without hepatic
impairment.1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15-30°C).1
Actions
• Selectively inhibits conversion of androgens to estrogens.1, 2, 6

• Decreased serum and tumor concentrations of estrogen inhibit breast tumor growth and delay
disease progression.1, 4
• Does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.1, 6
Advice to Patients
• Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.1
• Importance of informing clinicians of any existing or contemplated concomitant therapy,
including prescription and OTC drugs, as well as any concomitant illnesses.1
• Risk of osteoporosis.a, 29 Life-style changes (e.g., weight-bearing exercise, abstinence from
smoking, moderation of alcohol consumption) and dietary supplementation with calcium and
vitamin D advised.25, 29, 37
breast-feed; warn of potential hazard to the fetus in cases of inadvertent exposure of pregnant
women to letrozole.1
Preparations
Letrozole
Oral Tablets, film-coated 2.5 mg Femara® Novartis
Comparative Pricing
Femara 2.5MG Tablets (NOVARTIS): 10/$188.98 or 30/$516.96
Administration.
Reloxifen
Raloxifene (Systemic)
Estrogen agonist-antagonist; a nonsteroidal benzothiophene derivative.1, 2, 3, 13, 14, 15, 16, 17, 55, 69, 70
Class: 68:16.12 Estrogen Agonists-Antagonists; hs900 (VA primary)
Brands: Evista®
Generic Name: Raloxifene Hydrochloride

Chemical Name: 6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-
piperidinoethoxy)phenyl ketone hydrochloride
Molecular Formula: C28H27NO4S•ClH
Investigational Drug Number: LY156758
Synonym: Keoxifene Hydrochloride
Boxed Warning
• Increased risk for DVT and pulmonary embolism.1 Contraindicated in women with active or past
episodes of venous thrombosis.1 (See Contraindications and Cardiovascular Effects under
Cautions.)
• Increased risk of fatal stroke reported in women with CHD or increased risk for CHD.1 Weigh
risks versus benefits in women at risk for stroke.1 (See Cardiovascular Effects under Cautions.)
Uses
Osteoporosis
Prevention of osteoporosis in postmenopausal women.1, 2, 3, 4, 5, 6, 7, 16, 17, 23, 55, 69, 108
Treatment of osteoporosis in postmenopausal women.1, 53, 69, 98, 99, 108
Use supplemental calcium and/or vitamin D concomitantly if daily dietary intake is considered
inadequate.1, 2, 3, 4, 5, 6, 7, 16, 17, 23, 55, 69, 108
Corticosteroid-induced Osteoporosis
May prevent or treat corticosteroid-induced bone loss .107 American College of

Rheumatology states that raloxifene can be offered to selected postmenopausal corticosteroid-
treated women who refuse hormone replacement therapy or other antiresorptive agents (e.g.,
bisphosphonates, calcitonin) or in whom such therapies are contraindicated.107
Breast Cancer
Reduction in the incidence of invasive breast cancer in postmenopausal women with
osteoporosis.1, 93, 100
Reduction in the incidence of invasive breast cancer in postmenopausal women at high risk for
developing the disease.1, 109, 113 Effect comparable to that of tamoxifen in reducing the risk of
invasive breast cancer (STAR trial).1, 109, 113 No effect on the risk of lobular carcinoma in situ or
ductal carcinoma in situ (STAR trial).113 Effect on breast cancer incidence in women with
BRCA1 or BRCA2 genetic mutations not established.1
Not indicated for the treatment of breast cancer or to reduce the risk of recurrence of breast
cancer.1 Not indicated for reduction in the risk of noninvasive breast cancer.1
Administration
Oral Administration
Administer orally once daily without regard to meals or time of day.1, 2, 55
Dosage
Available as raloxifene hydrochloride; dosage expressed in terms of the salt.1
Adults
Osteoporosis
>Prevention in Postmenopausal Women
Oral: 60 mg daily.1, 2, 55
>Treatment in Postmenopausal Women

Oral: 60 mg daily.1, 98
Breast Cancer
>Reduction in the Incidence of Invasive Breast Cancer
Oral: 60 mg daily.1 Optimum duration of therapy unknown.1
Cautions
Contraindications
• Active or past episodes of venous thrombosis, including DVT, pulmonary embolism, or retinal
vein thrombosis.1, 52
• Women who are or may become pregnant.1
• Lactating women.1
Warnings
Increased risk of venous thromboembolic events (e.g., DVT, pulmonary embolism).1, 55, 69, 72
Discontinue raloxifene ≥72 hours before and during prolonged immobilization (e.g., postsurgery
recovery, prolonged bed rest); resume therapy once patient is fully ambulatory.1, 52
Assess potential benefit versus risk in women at risk of thromboembolic disease secondary to
CHF, superficial thrombophlebitis, or active malignancy.1, 2
Increased risk for fatal stroke reported in women with CHD or increased risk for CHD (RUTH
study).1, 115 Assess potential benefit versus risk in women at risk of stroke secondary to history of
stroke or TIA, atrial fibrillation, hypertension, or cigarette smoking.1
Not indicated for the primary or secondary prevention of cardiovascular disease.1

May cause fetal harm.1, 58, 59, 60, 61, 62, 63 Embryotoxic and teratogenic effects demonstrated in
animals.1, 60, 61 If inadvertently used during pregnancy or if patient becomes pregnant, apprise of
potential fetal hazard.1 (See Contraindications.)
General Precautions
Use in Premenopausal Women
Not indicated.1 Safety not established.1
Effects on Lipids
Potential for increased serum triglyceride concentrations in women with a history of substantial
hypertriglyceridemia during oral estrogen therapy; monitor serum triglycerides in these women.1
Effects on the Breast

Not studied in women with a history of breast cancer.1
Investigate unexplained breast abnormality.1 Does not eliminate risk of breast cancer.1
Use in Men
Safety and efficacy not evaluated.1
GU Effects
Not associated with endometrial proliferation.1 Investigate unexplained uterine bleeding.1
Pregnancy
Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under
Cautions.)
Lactation
Contraindicated.1
Not known whether raloxifene is distributed into milk.1

Pediatric Use
Not indicated.1
Geriatric Use
No substantial differences in safety, efficacy, or pharmacokinetic profile relative to younger
adults.1
Hepatic Impairment
Use with caution; safety and efficacy not established in patients with hepatic impairment.1 (See
Special Populations under Pharmacokinetics.)
Renal Impairment
Use with caution in patients with moderate to severe renal impairment; safety and efficacy not
established in these patients.1 (See Special Populations under Pharmacokinetics.)
Hot flushes (flashes), leg cramps, peripheral edema, flu-like syndrome, arthralgia, sweating.1, 2,
23, 69, 72, 88, 93, 96, 98
Interactions
Metabolism apparently not mediated by CYP isoenzymes.1
Protein-bound Drugs
Concomitant administration with other highly protein-bound drugs not expected to affect plasma
raloxifene concentrations.1 Caution advised if used concomitantly with other highly protein-
bound drugs.1
Specific Drugs

Ampicillin: Decreased peak plasma
raloxifene concentrations; no change in
Can be administered
Amoxicillin and ampicillin systemic exposure to raloxifene1
concomitantly1
Amoxicillin: No change in raloxifene
concentrations1
Decreased absorption and enterohepatic
Concomitant
cycling of raloxifene with concomitant
Anion-exchange resins administration with
cholestyramine administration; similar
(cholestyramine) cholestyramine not
interaction expected with other anion-
recommended1, 52
exchange resins1
Antacids (aluminum- and
No change in systemic exposure of Can be administered
magnesium-containing,
raloxifene1 concomitantly1
calcium carbonate)
Anticoagulants, oral Decreased warfarin effects; no effect on Monitor PT carefully1
warfarin pharmacokinetics observed1
Antilipemic agents Concomitant use not specifically studied1
Potential for altered protein binding of
Diazepam Caution advised1
diazepam1
Diazoxide Caution advised1
diazoxide1
Can be administered
Digoxin No change in digoxin pharmacokinetics1
concomitantly1
Concomitant use not
Estrogens Not studied1
recommended1
No substantial change in plasma raloxifene
Gemfibrozil
concentrations1
Lidocaine Caution advised1
lidocaine1
Can be administered
No change in methylprednisolone
Methylprednisolone concomitantly with
pharmacokinetics1
corticosteroids1
Phenytoin No change in protein binding of phenytoin1
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed from GI tract; 60% of an oral dose is absorbed, but absolute bioavailability as
unchanged drug is only 2% because of extensive first-pass glucuronidation.1, 27, 33, 34, 35, 45, 69
Following oral administration, peak plasma concentrations achieved at 6 hours (raloxifene) and 1
hour (glucuronide conjugates).33, 35
Food
High-fat meal increases peak plasma concentration and extent of absorption of raloxifene, but
does not substantially affect systemic exposure.1
Special Populations
Plasma raloxifene concentrations are 150% higher in patients with cirrhosis (Child-Pugh class A)
and total serum bilirubin concentrations of 0.6-2 mg/dL than in individuals with normal hepatic
function.1 Pharmacokinetics not studied in individuals with moderate or severe hepatic
impairment.1
Plasma raloxifene concentrations in those with mild renal impairment are similar to values in
women with normal renal function.1, 96 AUC of raloxifene is 122% higher in individuals with
moderate renal impairment (Clcr 31-50 mL/minute) or severe renal impairment (Clcr ≤30
mL/minute) than in individuals with normal renal function.1
Distribution

Raloxifene and its monoglucuronide conjugates: >95%.1, 69, 96 Raloxifene binds to albumin and
α1-acid glycoprotein but not to testosterone-estradiol binding globulin (sex hormone binding
globulin).1
Elimination
Metabolism
Undergoes extensive first-pass metabolism to glucuronide conjugates.1, 27, 33, 34, 35, 36, 55 Does not
appear to be metabolized by CYP isoenzymes.1 Conjugates converted back to the parent drug in
various tissues.1, 27
Elimination Route
Excreted principally in feces as unabsorbed drug and via biliary elimination as glucuronide
conjugates (subsequently metabolized by bacteria in GI tract to the parent drug).1, 45, 55, 69, 96
Half-life
32.5 hours.1, 55
Stability
Storage
Oral
Tablets
20-25°C.1
Actions
• Selective estrogen receptor modulator (SERM); exhibits estrogen agonist activity on bone, but
estrogen antagonist activity on breast and uterine tissue.1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 14, 15, 16, 17, 18, 21, 28, 69,
70, 88, 89, 101
• Differs chemically and pharmacologically from naturally occurring estrogens, synthetic steroidal
and nonsteroidal compounds with estrogenic activity, and agents described as antiestrogens (e.g.,
clomiphene, tamoxifen, toremifene).4, 13, 14, 15, 16, 17
• In postmenopausal women or women who have undergone oophorectomy, principal action in
bone is to decrease the rate of bone resorption, thus slowing the rate of bone loss.1, 2, 3, 4, 5, 6, 7, 16,
17, 19, 20, 23, 37
• Inhibits estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro.7, 16, 17,
43, 69
Advice to Patients
• Importance of providing patient a copy of manufacturer's patient information.1

• Risk of venous thromboembolic events.1 Notify clinician if signs or symptoms of thromboembolic
disorder occur.52 Avoid prolonged restrictions in movement while traveling.1, 52 Discontinue
raloxifene ≥72 hours before and during prolonged immobilization (e.g., postsurgery recovery,
prolonged bed rest).1
• Potential for increased incidence of hot flushes (flashes); drug is not effective in reducing hot
flushes associated with estrogen deficiency.1
• When used for osteoporosis, importance of taking supplemental calcium and/or vitamin D if daily
dietary intake is inadequate.1 Importance of weight-bearing exercise and modification of other
risk factors for osteoporosis (e.g., smoking, alcohol intake) if needed.1
• When used to reduce the incidence of invasive breast cancer, advise patient regarding benefits and
risks of therapy as well as appropriate indications.1 Need for regular breast examinations and
mammograms.1
• Importance for women who are or may become pregnant or who are lactating to avoid taking the
drug.1
prescription and OTC drugs, as well as any concomitant illnesses.1
Preparations
Raloxifene Hydrochloride
Oral Tablets, film-coated 60 mg Evista® Lilly
Comparative Pricing
Evista 60MG Tablets (LILLY): 30/$139.99 or 90/$369.95
Administration.
Exemestane
Exemestane (Systemic)
Antineoplastic agent; irreversible, selective steroidal aromatase inhibitor (type I), structurally
related to the natural substrate androstenedione.1, 2, 3, 4, 5, 6
Brands: Aromasin®
Generic Name: Exemestane

CAS Number: 107868-30-4
Molecular Formula: C20H24O2
Investigational Drug Number: FCE 24304, PNU 155971
Uses
Breast Cancer
Treatment of advanced breast cancer in postmenopausal women whose disease has progressed
following tamoxifen therapy.1
Administration
Oral Administration
Administer orally after a meal.1
Dosage
Adults
Breast Cancer
Oral: 25 mg once daily; continue until tumor progression is evident.1
Prescribing Limits
Adults
Dosages >25 mg daily not shown to provide substantially greater suppression of plasma
estrogens but may increase adverse effects.1, 2, 3
Special Populations
Hepatic Impairment
Dosage adjustment does not appear to be necessary.1 (See Special Populations under
Pharmacokinetics.)
Renal Impairment
Dosage adjustment does not appear to be necessary.1 (See Special Populations under
Pharmacokinetics.)
Cautions
Contraindications
• Known hypersensitivity to exemestane or any ingredient in the formulation.1
Warnings
Possible fetal harm; embryotoxic in rats and embryotoxic and abortifacient in rabbits.1 If used
during pregnancy, apprise of potential hazard to fetus and potential risk for loss of the
pregnancy.1
General Precautions
Premenopausal Women
Not recommended for use in premenopausal women.1 Possible incomplete estrogen suppression
and reflex increases in gonadotropin levels (ovarian hyperstimulation syndrome).6
Estrogenic Agents
Do not administer concomitantly with exemestane.1 (See Estrogenic Agents under Interactions.)
Lymphocytopenia
Risk of grade 3 or 4 lymphocytopenia; no substantial increase in viral infections and no
opportunistic infections observed in clinical studies.1
Pregnancy
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1 Caution advised if
a nursing woman is inadvertently exposed to the drug.1
Pediatric Use
Not indicated; safety and efficacy not established.1
Geriatric Use
No special precautions.1
Hepatic Impairment
Safety of chronic administration not established.1
Renal Impairment
Safety of chronic administration not established.1
Hot flushes (flashes), nausea, fatigue, increased sweating, excessive weight gain, pain, mental
depression, insomnia, anxiety, dyspnea, dizziness, headache, edema, vomiting, flu-like
symptoms, abdominal pain, anorexia, coughing, hypertension, constipation.1
Interactions
Metabolized by CYP3A4.1 Does not inhibit CYP1A2, 2C9, 2D6, 2E1, or 3A4.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of CYP3A4; potential pharmacokinetic interaction (possible increased or

decreased serum exemestane concentrations).1 However, based on experience with concomitant
ketoconazole (potent CYP3A4 inhibitor), clinically important interactions with CYP3A4
inhibitors unlikely.1
Estrogenic Agents
Potential antagonistic pharmacologic effects.1
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed following oral administration, with peak concentrations in women with breast
cancer or healthy women attained within about 1.2 or 2.9 hours, respectively.1
Steady-state plasma concentrations achieved in approximately 7 days.1
Food
High-fat meal increases plasma exemestane concentrations by approximately 40%.1
Distribution
Extent
Extensively distributed into tissues.1
Crosses placenta.
Distributed into milk in animals; not studied in pregnant or nursing women.1

90% (mainly α1-acid glycoprotein and albumin).1
Elimination
Metabolism
Extensively metabolized via CYP3A4 and aldoketoreductases; metabolites are inactive or inhibit
aromatase with decreased potency compared with parent drug.1 One metabolite, 17-
hydroexemestane, may have androgenic activity.1
Elimination Route
Excreted similarly (42%) in both urine and feces; <1% excreted as unchanged drug in urine.1
Half-life
Approximately 24 hours.1
Special Populations
In patients with moderate or severe hepatic or renal impairment, AUC is approximately 3 times
higher than in healthy individuals.1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15-30°C).1
Actions
• Acts as a false substrate and is converted by aromatase to reactive alkylating intermediates that
bind covalently to the substrate binding site of the enzyme; this irreversible binding to the active
site of aromatase results in its inactivation (i.e., "suicide" inhibition).1, 2, 4, 5, 6
• Selectively inhibits conversion of androgens to estrogens;1, 2, 4, 5, 6 resulting reduction in serum
and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.1, 6
• Selectively inhibits synthesis of estrogens; does not affect synthesis of adrenal corticosteroid,
aldosterone, or thyroid hormone.1, 2, 3, 6
• Dose-dependent decrease in sex hormone binding globulin (SHBG) observed with dosages ≥ 2.5
mg daily.1, 2
• Slight, dose-independent increases in serum LH and FSH concentrations observed even at low
dosages as result of negative feedback on the pituitary gland.1, 2, 3
• At dosages ≤25 mg daily, no clinically important effect on circulating concentrations of
testosterone, androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone
observed.1, 3
• At dosages ≥200 mg daily, testosterone and androstenedione concentrations are increased.1, 3 17-
Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may
become clinically important at high (e.g., 200 mg daily) dosages.1, 2, 3
Advice to Patients
• Importance of adherence to dosing and medical or laboratory appointment schedules.1

prescription and OTC drugs, as well as concomitant illnesses.1
breast-feed; warn of potential hazard to the fetus in cases of inadvertent exposure of pregnant
women to exemestane.1
Preparations
Exemestane
Oral Tablets 25 mg Aromasin® Pfizer
Comparative Pricing
Aromasin 25MG Tablets (PFIZER U.S.): 30/$406.97 or 90/$1189.92

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The mechanisms by which cancers occur are incompletely understood.

Drug or Hormone Type of Cancer

Adjuvant Endocrine Therapy

Tamoxifen metabolism.131 Widths of the arrows approximate allocation of parent compound to

Toremifene is another marketed antiestrogen whose primary advantage is a lower estrogenic-to-

Sidebar: Clinical Controversy

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.128

Class: 10:00 Antineoplastic Agents; an500 (VA primary)

Long-term effects not established.a

Dosage and Administration

Available as tamoxifen citrate; dosage expressed in terms of tamoxifen.128

>Ductal Carcinoma in Situ

>Metastatic Breast Cancer

>Reduction in the Incidence of Breast Cancer in Women at High Risk

• Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

Effects on the Uterus

Fetal/Neonatal Morbidity and Mortality

Common Adverse Effects

Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128

A substrate of CYP3A, 2C9, 2D6.a

Increased risk of thromboembolic events.128

Drug Interaction Comments

Not known whether tamoxifen is distributed into milk.128

N-Desmethyltamoxifen: 9-14 days.128, 139, 145

Nolvadex 20MG Tablets (ASTRAZENECA): 30/$120.99 or 60/$239.98

Tamoxifen Citrate 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$21.99 or

Antineoplastic agent; selective aromatase inhibitor (type II).1, 16, b

Class: 10:00 Antineoplastic Agents; an900 (VA primary)

Generic Name: Anastrozole

First-line therapy for hormone receptor-positive (i.e., estrogen receptor-positive, progesterone

Not recommended as adjuvant therapy in postmenopausal women with hormone-receptor-

receptor-positive early-stage breast cancer in postmenopausal women.20, 49

positive early-stage breast cancer in postmenopausal women.54

breast cancer in combination with a luteinizing hormone-releasing hormone (LHRH)

puberty ; however, manufacturer states that efficacy is not established.b

Dosage and Administration

>Adjuvant Treatment of Early Breast Cancer

Not studied in patients with severe hepatic impairment.1, b

• Known hypersensitivity to anastrozole or any ingredient in the formulation.1, b

Monitor BMD prior to and at annual intervals during therapy.36, 37, c

Fetal/Neonatal Morbidity and Mortality

puberty ;b however, efficacy not established for these indications.b

Common Adverse Effects

Drug Interaction Comment

Possible decreased plasma

Steady-state plasma concentrations achieved in about 7 days.1, b

Not known whether anastrozole is distributed into milk.1, b

Plasma Protein Binding

• Selectively inhibits conversion of androgens to estrogens.1, 6, 14

• Importance of providing patient with a copy of the manufacturer's patient information.c

Arimidex 1MG Tablets (ASTRAZENECA): 30/$455.01 or 90/$1308.9

Antineoplastic agent; a nonsteroidal estrogen agonist-antagonist that is structurally and

Class: 10:00 Antineoplastic Agents; an500 (VA primary)

Generic Name: Toremifene Citrate

Palliative treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor

Efficacy in treatment of advanced breast cancer in men not demonstrated.29, 30

Because of demonstrated cross-resistance with tamoxifen, usefulness of toremifene as second-

Dosage and Administration

Available as toremifene citrate; dosage expressed in terms of toremifene.1

• Known hypersensitivity to toremifene or any ingredient in the formulation.1

Monitor serum calcium concentrations periodically during therapy.1

Effects on the Uterus

Fetal/Neonatal Morbidity and Mortality

Cardiac failure, MI, arrhythmia, angina pectoris, and edema reported.1