Arimidex® (Advanced Breast Cancer)
Anastrozole
Nonsteroidal Aromatase Inhibitor
AstraZeneca
http://www.astrazeneca-us.com/default.asp
Arimidex Monograph PDF download here.
CPS:PIS_m065400
Pharmacology
Many breast cancers have estrogen receptors and
growth of these tumors can be stimulated by estrogens. In postmenopausal women,
the principal source of circulating estrogen (primarily estrone) is conversion
of adrenally generated androstenedione to estrone by aromatase in peripheral
tissues, such as adipose tissue, with further conversion of estrone to
estradiol. Many breast cancers also contain aromatase; the importance of
tumor-generated estrogens is uncertain.
Treatment of breast
cancer has included efforts to decrease estrogen levels by ovariectomy
premenopausally and by use of anti-estrogens and progestational agents both
pre- and postmenopausally, and these interventions lead to decreased tumor mass
or delayed progression of tumor growth in some women.
Anastrozole is a potent
and selective nonsteroidal aromatase inhibitor. It significantly lowers serum
estradiol concentrations and has no detectable effect on formation of adrenal
corticosteroids or aldosterone.
The relationship
between dose and response, measured as suppression of serum estradiol, was
studied in postmenopausal women. Daily doses of anastrozole at 1 mg for
14 days produced estradiol suppression of greater than 80%. Suppression of
serum estradiol was maintained for up to 6 days after cessation of daily
dosing with 1 mg anastrozole.
In a study of 14
postmenopausal women diagnosed with locally advanced (Stage T3-T4) breast
cancer with noninflammatory, estrogen-receptor positive tumors, anastrozole was
shown to be a potent suppressor of intratumoral estrogen levels. Following use
as a 15-week primary systemic treatment (prior to any local surgery and/or
radiotherapy), anastrozole-suppressed intratumoral concentrations of estradiol
(E2), estrone (E1) and estrone sulfate (E1S)
to mean values of 11.1%, 16.7% and 26.6%, respectively, of baseline levels.
Three patients had intratumoral levels of E2, E1 and E1S
suppressed below assay detection limits.
Because of its
pharmacological action, patients with estrogen and/or progesterone
receptor-positive disease are the most appropriate population for anastrozole
therapy (see Clinical Experience).
The selectivity of
anastrozole to the aromatase enzyme, rather than other cytochrome P450 enzymes
controlling glucocorticoid and mineralocorticoid synthesis in the adrenal
gland, has been established. Furthermore, provocative stimulation of the
adrenal glands by ACTH in subjects under treatment with anastrozole up to
10 mg, produced a normal response in terms of cortisol and aldosterone
secretion. Therefore, patients treated with anastrozole do not require
glucocorticoid or mineralocorticoid replacement therapy.
Anastrozole does not
possess direct progestogenic, androgenic or estrogenic activity and does not
interfere with secretion of thyroid stimulating hormone (TSH).
Pharmacokinetics
Inhibition of aromatase activity is primarily
due to anastrozole, the parent drug. Absorption of anastrozole is rapid and
maximum plasma concentrations typically occur within 2 hours of dosing
under fasted conditions. Studies with radiolabeled drug have demonstrated that
orally administered anastrozole is well absorbed into the systemic circulation.
Food reduces the rate but not the overall extent of anastrozole absorption.
Anastrozole is
eliminated slowly with a plasma elimination half-life of approximately
50 hours in postmenopausal women. The pharmacokinetics of anastrozole are
linear over the dose range of 1 to 20 mg and do not change with
repeated dosing. Consistent with the 50-hour plasma elimination half-life,
plasma concentrations of anastrozole approach steady-state concentrations after
7 days of once daily dosing and are approximately 3- to 4-fold higher
than the concentrations observed after a single dose of anastrozole. The
protein binding of anastrozole to plasma proteins is about 40% and independent
of concentration over a range which includes therapeutic concentrations.
Studies in postmenopausal
women with radiolabeled anastrozole demonstrated that elimination occurs
primarily via metabolism (approximately 85%) and to a lesser extent renal
excretion of unchanged anastrozole (approximately 11%). Metabolism of
anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three
metabolites of anastrozole (triazole, a glucuronide conjugate of
hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have
been identified in human plasma or urine. Several minor (less than 5% of the
radioactive dose) metabolites excreted in the urine have not been identified.
The major metabolite of anastrozole in the circulation, triazole, lacks
pharmacologic activity.
Special Populations: Geriatrics: Anastrozole
pharmacokinetics have been investigated in postmenopausal female volunteers and
patients with breast cancer. The pharmacokinetics were similar in volunteers
and in patients and no age-related effects were seen.
Japanese Patients: Anastrozole pharmacodynamics
and pharmacokinetics have been studied in healthy, postmenopausal women in
Japan, dosed for 16 days. The pharmacodynamic effect and pharmacokinetics of
anastrozole 1 mg daily were similar in Japanese and Caucasian volunteers, and
there was no indication that there would be any clinically significant
differences in therapeutic responses to anastrozole between Japanese and
Caucasian patients with breast cancer.
Renal Insufficiency: Anastrozole
pharmacokinetics have been investigated in subjects with renal insufficiency.
Anastrozole renal clearance decreased proportionately with creatinine clearance
and was approximately 50% lower in volunteers with severe renal impairment
(creatinine clearance less than 30 mL/min/1.73 m2 or
0.5 mL/sec/1.73 m2) compared to controls. Because renal clearance
is not a significant pathway of elimination, the apparent oral clearance of
anastrozole is unchanged even in severe renal impairment. Dosage adjustment in
patients with renal dysfunction is not necessary (see Dosage).
Hepatic Insufficiency: Anastrozole
pharmacokinetics have been investigated in subjects with stable hepatic
cirrhosis related to alcohol abuse. The apparent oral clearance of anastrozole
was approximately 30% lower in subjects with hepatic cirrhosis than in control
subjects with normal liver function. However, plasma anastrozole concentrations
in the subjects with hepatic cirrhosis are within the range of concentrations
seen in normal subjects across all clinical trials. Dosage adjustment in
patients with hepatic dysfunction is not necessary (see Dosage).
Drug Interactions
Anastrozole inhibits reactions catalyzed by
cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which are
approximately 30 times higher than the mean plasma steady-state Cmax
values observed following a 1 mg daily dose. Anastrozole has no inhibitory
effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro.
Administration of a single 30 mg or multiple 10 mg doses of
anastrozole to subjects had no effect on the clearance of antipyrine or urinary
recovery of antipyrine metabolites. Based on these in vitro and in vivo
results, it is unlikely that the administration of anastrozole 1 mg will
result in clinically significant inhibition of cytochrome P450-mediated
metabolism of coadministered drugs.
The effect of
anastrozole on tamoxifen (20 mg daily) pharmacokinetics has been studied in
postmenopausal women with early breast cancer who were already receiving
tamoxifen as adjuvant therapy. There was no evidence of anastrozole having any
significant effect on blood levels of tamoxifen compared to placebo (p=0.919)
(see Precautions).
The pharmacokinetics
and anticoagulant activity of warfarin (25 mg) coadministered with
anastrozole (1 mg daily) have been studied in healthy male volunteers. The mean
plasma concentrations of anastrozole achieved throughout the warfarin dosing
and sampling period were within the range seen in postmenopausal women with
advanced breast cancer taking the clinically recommended dose of the drug.
Overall, there was no evidence to suggest that anastrozole has any clinically
relevant effects on the pharmacokinetics or anticoagulant activity of warfarin.
Clinical Experience
Treatment of Postmenopausal Women with Advanced
Breast Cancer: Anastrozole was studied in 2, double-blind, controlled trials of
similar design (0030, a North American study; 0027, a predominantly European
study) in 1021 postmenopausal women with advanced breast cancer. Eligible
patients were randomized to receive a single daily dose of either anastrozole
1 mg or tamoxifen 20 mg. The trials were designed to allow data to be
pooled.
Demographics and other
baseline characteristics were similar for the 2 treatment groups, however,
there were differences in hormone receptor status between the 2 trials. In
Trial 0030, 88.3% of anastrozole-treated patients and 89.0% of
tamoxifen-treated patients were known to be estrogen- and/or
progesterone-receptor positive, compared to 45.3% and 43.9% (respectively) of
patients in Trial 0027.
Anastrozole was shown
to be at least as effective as tamoxifen for the primary endpoints of time to
progression and objective response rate. In Trial 0030, a non-protocolled
analysis indicated that anastrozole had a statistically significant advantage
over tamoxifen (p=0.005) for time to progression (11.1 months versus
5.6 months, respectively) (see Figure 1). Trial 0027 showed anastrozole
to be at least as effective as tamoxifen for time to progression
(8.2 months versus 8.3 months, respectively) (see Figure 2) and objective
response rate. The combined data from the 2 trials showed anastrozole to
be numerically superior to tamoxifen for time to progression (8.5 months versus
7.0 months, respectively) (see Figure 3). In a retrospective data analysis,
patients from Trial 0027 who were known to be estrogen- and/or
progesterone-receptor positive were shown to have longer median times to
progression (271 days) when treated with anastrozole than those treated
with tamoxifen (237 days) (see Figure 4). In addition, combined data from both
trials, for patients who were estrogen- and/or progesterone-receptor positive,
showed median times to progression of 10.7 months versus 6.4 months for
anastrozole-versus tamoxifen-treated patients: (two sided, p=0.022,
retrospective analysis). These subgroup analyses support the results of Trial
0030 in suggesting numerical superiority for anastrozole over tamoxifen in
patients known to be estrogen- and/or progesterone-receptor positive.
Furthermore, these analyses demonstrate that patients with estrogen and/or progesterone
receptor positive tumours are clearly the most appropriate population for
ARIMIDEX therapy.
Figure 1:
ARIMIDEX
Kaplan-Meier Plot of Time to Progression—Intent
to Treat Approach—Trial 0030 all patients
Figure 2:
ARIMIDEX
Kaplan-Meier Plot of Time to Progression—Intent
to Treat Approach—Trial 0027 all patients
Figure 3:
ARIMIDEX
Kaplan-Meier Plot of Time to Progression—Intent
to Treat Approach—Trials 0030 and 0027 combined
Figure 4:
ARIMIDEX
Kaplan-Meier Plot of Time to Progression—Intent
to Treat Approach—Trial 0027 estrogen/progesterone- receptor positive patients
only
Results from the
secondary endpoints of time to treatment failure, duration of response, and
duration of clinical benefit were supportive of the results of the primary
efficacy endpoints. The number of patients who experienced clinical benefit
(best objective response of complete response [CR], partial response [PR] or
stable disease [SD] ≥ 24 weeks) is shown in Table 1.
CPS:Arimidexadvanced_t1Click here for Table 1
Table 1: ARIMIDEX
Patients Who Experienced Clinical Benefit
|
Clinical Benefit
|
Number (%) of Patients
|
|
Trial 0030
|
Trial 0027
|
Combined Trials
|
|
|
Anastrozole
1 mg
(n=171)
|
Tamoxifen
20 mg
(n=182)
|
Anastrozole
1 mg
(n=340)
|
Tamoxifen
20 mg
(n=328)
|
Anastrozole
1 mg
(n=511)
|
Tamoxifen
20 mg
(n=510)
|
|
|
CR
|
5 (2.9)
|
5 (2.7)
|
19 (5.6)
|
16 (4.9)
|
24 (4.7)
|
21 (4.1)
|
|
|
PR
|
31 (18.1)
|
26 (14.3)
|
93 (27.4)
|
91 (27.7)
|
124 (24.3)
|
117 (22.9)
|
|
|
SD ≥ 24 weeks
|
65 (38.0)
|
52 (28.6)
|
79 (23.2)
|
75 (22.9)
|
144 (28.2)
|
127 (24.9)
|
|
|
Total
|
101 (59.1)a
|
83 (45.6)a
|
191 (56.2)
|
182 (55.5)
|
292 (57.1)
|
265 (52.0)
|
|
a Two-sided p=0.0098, Retrospective
analysis.
Legend: CR=complete response.
PR=partial response.
SD=stable disease.
There were too few
deaths occurring across treatment groups of both trials to assess overall
survival differences at the time of data analysis.
Treatment of Postmenopausal Women with Advanced
Breast Cancer who had Disease Progression following Tamoxifen Therapy:
Anastrozole was studied in 2 well-controlled clinical trials (0004, a
North American study; 0005, a predominantly European study) in postmenopausal
women with advanced breast cancer who had disease progression following tamoxifen
therapy. Most patients were estrogen receptor-positive; a smaller fraction was
estrogen receptor-unknown or estrogen receptor-negative. Eligible patients were
randomized to receive either a single daily dose of 1 or 10 mg of
anastrozole, or megestrol acetate 40 mg 4 times a day. The studies
were double-blinded with respect to anastrozole. Approximately 1/3 of the
patients in each treatment group in both studies had either an objective
response or stabilization of their disease for greater than 24 weeks. Hazard
ratios for time to progression and odds ratios for response rates were
calculated for the pooled studies and were shown to be similar. After analysis
of mature data involving 473 patients among 764 randomized
participants, the hazard ratios for survival demonstrated a significant
prolongation of survival in the 1 mg anastrozole group compared to
hormonal treatment with megestrol acetate. See Table 2.
CPS:Arimidexadvanced_t2Click here for Table 2
Table 2: ARIMIDEX
Analysis of Time to Death for Patients in Trials
0004 and 0005 Combined
|
|
Trial Treatment
|
Hazard Ratioa
, (97.5% CI), and p-valuesb
|
|
Time to Death
|
Anastrozole
1 mg
|
Anastrozole
10 mg
|
MA
|
Anastrozole
1 mg vs MA
|
Anastrozole
10 mg vs MA
|
|
|
Number of Patients who Died (%)
|
151 of 263
(57.4)
|
151 of 248
(60.9)
|
171 of 253
(67.6)
|
|
|
|
|
2-year Survival Rate
|
56.1%
|
54.6%
|
46.3%
|
|
|
|
|
Median Time to Death (months)
|
26.7
|
25.5
|
22.5
|
0.78
(0.6040 to 0.9996)
p=0.0248c
|
0.83
(0.6452 to 1.0662)
p=0.0951c
|
|
a Hazard ratio greater than 1.00
indicated that the first treatment is associated with shorter time to death
than is the second treatment.
b The critical p-value for
statistical significance is 0.025.
c Calculated using Cox's regression
model.
Legend: Cl=Confidence interval.
MA=Megestrol acetate.
Patients with estrogen
receptor-negative disease rarely responded to anastrozole, but there were too
few patients in this group for a meaningful analysis.
Indications
For hormonal treatment of advanced breast cancer
in postmenopausal women.
Contraindications
Patients with hypersensitivity to the drug or
any of its components.
Pregnancy
Anastrozole is contraindicated in pregnant
women.
Lactation
Anastrozole is contraindicated in lactating
women.
Warnings
Premenopausal Women: Anastrozole is not
recommended for use in premenopausal women as safety and efficacy have not been
established in this group of patients.
Pregnancy
There are no adequate and well-controlled
studies in pregnant women using anastrozole. If the patient becomes pregnant
while receiving this drug, the patient should be apprised of the potential
hazard to the fetus or potential risk for loss of the pregnancy (see
Contraindications).
Reproductive Toxicology: Anastrozole has been
found to cross the placenta following oral administration of 0.1 mg/kg in
rats and rabbits. Studies in both rats and rabbits at doses equal to or greater
than 0.1 and 0.02 mg/kg/day, respectively (about ¾ and ⅓ ,
respectively, the recommended human dose on a mg/m2 basis),
administered during the period of organogenesis showed that anastrozole
increased pregnancy loss (increased pre- and/or postimplantation loss,
increased resorption and decreased numbers of live fetuses). Effects were dose
related in rats. Placental weights were significantly increased in rats at
doses of 0.1 mg/kg/day or more.
Evidence of
fetotoxicity, including delayed fetal development (i.e., incomplete
ossification and depressed fetal body weights), was observed in rats
administered doses of 1 mg/kg/day (about 7 times the recommended
human dose on a mg/m2 basis). There was no evidence of
teratogenicity in rats administered doses up to 1 mg/kg/day. In rabbits,
anastrozole caused pregnancy failure at doses equal to or greater than
1 mg/kg/day (about 16 times the recommended human dose on a mg/m2
basis). There was no evidence of teratogenicity in rabbits administered
0.2 mg/kg/day (about 3 times the recommended human dose on
a mg/m2 basis).
Children
The safety and efficacy of anastrozole in
pediatric patients have not been established.
Severe Hepatic/Renal Impairment
Anastrozole has not been investigated in
patients with severe hepatic or severe renal impairment. The potential
risk/benefit to such patients should be carefully considered before
administration of anastrozole (see Pharmacology, Special Populations, Renal
Insufficiency, Hepatic Insufficiency and Dosage).
Use in Women who are Osteoporotic or at High
Risk of Developing Osteoporosis
The use of estrogen lowering agents, including
ARIMIDEX, may cause a reduction in bone mineral density. Women with
osteoporosis, or at high risk of osteoporosis, should have their bone mineral
density formally assessed by bone densitometry e.g., DEXA scanning at the
commencement of treatment and at regular intervals thereafter. Treatment or
prophylaxis for osteoporosis should be initiated according to local clinical
practice and carefully monitored.
Other
Anastrozole has not been investigated in
patients with any degree of brain or leptomeningeal involvement or with
pulmonary lymphangitic disseminated disease.
Precautions
General
Anastrozole should be administered under the
supervision of a qualified physician experienced in the use of anti-cancer
agents.
Drug Interactions
Antipyrine, cimetidine, tamoxifen and warfarin
clinical interaction studies indicate that the coadministration of anastrozole
with other drugs is unlikely to result in clinically significant drug
interactions mediated by cytochrome P450 (see Pharmacology, Drug
Interactions). A review of AstraZeneca's global clinical trial safety database
did not reveal evidence of clinically significant interactions in patients
treated with ARIMIDEX who also received other commonly prescribed drugs.
Drug/Laboratory Test Interactions
Anastrozole has not been observed to interfere
with routine clinical laboratory tests results.
Occupational Hazards
Effect on Ability to Drive and Use Machinery:
Anastrozole is unlikely to impair the ability of patients to drive and operate
machinery. However, asthenia and somnolence have been reported with the use of
anastrozole and caution should be observed when driving or operating machinery
while such symptoms persist.
Adverse Effects
Anastrozole has generally been well tolerated.
Adverse events have usually been mild to moderate with few withdrawals from
treatment due to undesirable events.
The pharmacological
action of anastrozole may give rise to certain expected effects. These include
hot flushes, vaginal dryness and hair thinning. Anastrozole may also be
associated with gastrointestinal disturbances (anorexia, nausea, vomiting and
diarrhea), asthenia, joint pain/stiffness, somnolence, headache or rash
including very rare (<0.1%) cases of mucocutaneous disorders such as
erythema multiforme, Stevens-Johnson syndrome and allergic reactions including
angioedema, urticaria and anaphylaxis.
Hepatic changes
(elevated gamma-GT or less commonly alkaline phosphatase) have been reported in
patients with advanced breast cancer, many of whom had liver and/or bone
metastases. A causal relationship for these changes has not been established.
Slight increases in total cholesterol have also been observed in clinical
trials with anastrozole.
Patients With Advanced Breast Cancer: Two
controlled clinical trials involving postmenopausal women with advanced breast
cancer compared treatment with tamoxifen (20 mg daily) versus treatment with
anastrozole (1 mg daily). Table 3 presents adverse events reported in these
trials with an incidence of greater than 5% in either treatment group,
regardless of causality.
CPS:Arimidexadvanced_t3Click here for Table 3
Table 3: ARIMIDEX
Number (%) of Patients With Adverse Eventa
|
Adverse Event
|
Anastrozole
1 mg
(n=506)
|
Tamoxifen
20 mg
(n=511)
|
|
Vasodilatation
|
128 (25.3)
|
106 (20.7)
|
|
Nausea
|
94 (18.6)
|
106 (20.7)
|
|
Asthenia
|
83 (16.4)
|
81 (15.9)
|
|
Pain
|
70 (13.8)
|
73 (14.3)
|
|
Back Pain
|
60 (11.9)
|
68 (13.3)
|
|
Cough Increased
|
55 (10.9)
|
52 (10.2)
|
|
Bone Pain
|
54 (10.7)
|
52 (10.2)
|
|
Dyspnea
|
51 (10.1)
|
47 (9.2)
|
|
Peripheral Edema
|
51 (10.1)
|
41 (8.0)
|
|
Pharyngitis
|
49 (9.7)
|
68 (13.3)
|
|
Constipation
|
47 (9.3)
|
66 (12.9)
|
|
Headache
|
47 (9.3)
|
40 (7.8)
|
|
Abdominal Pain
|
40 (7.9)
|
38 (7.4)
|
|
Diarrhea
|
40 (7.9)
|
33 (6.5)
|
|
Rash
|
38 (7.5)
|
34 (6.7)
|
|
Vomiting
|
38 (7.5)
|
36 (7.0)
|
|
Chest Pain
|
37 (7.3)
|
37 (7.2)
|
|
Flu Syndrome
|
35 (6.9)
|
30 (5.9)
|
|
Dizziness
|
30 (5.9)
|
22 (4.3)
|
|
Insomnia
|
30 (5.9)
|
28 (5.5)
|
|
Anorexia
|
26 (5.1)
|
46 (9.0)
|
|
Hypertension
|
25 (4.9)
|
36 (7.0)
|
|
Depression
|
23 (4.5)
|
32 (6.3)
|
|
Pelvic Pain
|
23 (4.5)
|
30 (5.9)
|
|
Hypertonia
|
16 (3.2)
|
26 (5.1)
|
|
Leucorrhea
|
9 (1.8)
|
31 (6.1)
|
a A patient may have more than 1
adverse event.
Based on results from
the established safety profiles of anastrozole and tamoxifen, the incidences of
9 prespecified adverse event categories, potentially causally related to one or
both therapies because of their pharmacology, were statistically analyzed. No
statistically significant differences were seen between treatment groups. The
results are shown in Table 4.
CPS:Arimidexadvanced_t4Click here for Table 4
Table 4: ARIMIDEX
Number (%) of Patientsa
|
Adverse Event Categories
|
Anastrozole
1 mg
(n=506)
|
Tamoxifen
20 mg
(n=511)
|
|
Tumor Flare
|
15 (3.0)
|
18 (3.5)
|
|
Vaginal Dryness
|
15 (3.0)
|
13 (2.5)
|
|
Weight Gain
|
|
