Arimidex

• Store Arimidex at 68°F to 77°F (20°C to 25°C).
• Keep Arimidex and all medicines out of the reach of children.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Contraindications

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

• Premenopausal women.1 (See Premenopausal Women under Cautions.)

• Pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Ischemic Cardiovascular Effects

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.1

Effects on Bone

Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.36

Bone mineral density (BMD) at lumbar spine and hip decreased in patients receiving anastrozole and increased in those receiving tamoxifen as initial (primary) adjuvant therapy.1 43 48 Incidence of fractures was higher with anastrozole versus tamoxifen during treatment, but not following completion of treatment.1 66

Evaluate all postmenopausal women initiating adjuvant aromatase inhibitor therapy for risk of osteoporotic fractures;70 71 73 determine BMD and assess other risk factors for fracture (e.g., age, low body mass index, family history of hip fracture, prior fragility fracture, history of cigarette smoking, excessive alcohol consumption, current or prior corticosteroid use).70 71 73 Closely monitor patients for changes in risk status during therapy, and assess BMD at regular intervals (e.g., every 1–2 years in those with osteopenia or osteoporosis).70 71 73 Consider other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria).70 71 73

Initiate appropriate therapy to prevent bone loss as clinically indicated.71 Base decision to initiate antiresorptive therapy (e.g., bisphosphonate, denosumab) on overall risk of fracture and rate of bone loss.70 71 72 73

Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and supplemental calcium and vitamin D recommended in all women receiving adjuvant anastrozole therapy.36 46 47 70 71 72 73

Lipid Effects

Increases in total serum cholesterol reported during therapy;1 consider monitoring serum cholesterol.1 46

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and fetotoxic in animals.1 Contraindicated in women who are or may become pregnant (i.e., premenopausal women).1 If inadvertently used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Sensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria) reported rarely.1 48

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether anastrozole is distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Has been used in clinical studies of adolescent boys 11–18 years of age with pubertal gynecomastia† and in girls 2 to <10 years of age with McCune-Albright syndrome and progressive precocious puberty†; however, efficacy not established for these indications.1

Geriatric Use

For adjuvant treatment of hormone receptor-positive early-stage breast cancer, efficacy (e.g., disease-free survival benefit) in women ≥65 years of age was less than efficacy observed in postmenopausal women <65 years of age.1

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 moderately greater efficacy observed for patients ≥65 years of age when used as first-line therapy for locally advanced or metastatic breast cancer.1

Premenopausal Women

Clinical benefit not established in premenopausal women with breast cancer.1 Contraindicated in premenopausal women.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment.1

Common Adverse Effects

Initial adjuvant therapy: Vasodilation, hot flushes (flashes), fatigue/asthenia, mood disturbance, pain, arthritis, arthralgia.1

Advanced-stage disease: GI disturbance (e.g., nausea), hot flushes, vasodilation, nausea, asthenia.1

• Importance of providing patient with a copy of the manufacturer’s patient information.1

• Risk of osteoporosis.1 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 Importance of BMD monitoring.1 71 73

• Risk of fetal harm if used during pregnancy.1 Contraindicated in premenopausal women.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., estrogens, raloxifene, tamoxifen), and OTC drugs, as well as any concomitant illnesses.1

• Increased risk of ischemic cardiovascular events in patients with preexisting ischemic heart disease.1

• Importance of immediately informing clinician if manifestations of a serious allergic reaction (e.g., swelling of face, lips, tongue, and/or throat; difficulty in swallowing and/or breathing) occur.1

• Risk of hypercholesterolemia.1 Importance of lipoprotein monitoring.1 46

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Anastrozole is used to treat certain types of breast cancer in women who have already stopped menstruating (postmenopausal). It is also used for women who have already had other cancer treatments (e.g., tamoxifen).

Many breast cancer tumors grow in response to estrogen. This medicine interferes with the production of estrogen in the body. As a result, the amount of estrogen that the tumor is exposed to is reduced, limiting the growth of the tumor.

This medicine is available only with your doctor's prescription.

• It is used to treat breast cancer in women after change of life.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low mood (depression), thoughts of killing yourself, nervousness, emotional ups and downs, thinking that is not normal, anxiety, or lack of interest in life.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of high calcium levels like weakness, confusion, feeling tired, headache, upset stomach and throwing up, hard stools (constipation), or bone pain.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• A burning, numbness, or tingling feeling that is not normal.
• Chest pain or pressure.
• A heartbeat that does not feel normal.
• Mood changes.
• Very bad dizziness or passing out.
• Passing urine more often.
• Pain when passing urine.
• Feeling very tired or weak.
• Swollen gland.
• Vaginal bleeding that is not normal.
• Vaginal itching or discharge.
• People who have ever had a block in their heart blood vessels (ischemic heart disease) may have more signs of problems with blood flow to the heart. Call your doctor right away if you have new or worse chest pain or shortness of breath.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flushing.
• Feeling tired or weak.
• Headache.
• Upset stomach or throwing up.
• Joint pain or swelling.
• Not able to sleep.
• Cough.
• Sore throat.
• Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Pregnancy and Premenopausal Women

Arimidex may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Arimidex is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using Arimidex. If Arimidex is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy [see Use in Specific Populations (8.1)].

Hypersensitivity

Arimidex is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria [see Adverse Reactions (6.2)].

Serious adverse reactions with Arimidex occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions (6.2)].

Common adverse reactions (occurring with an incidence of ≥10%) in women taking Arimidex included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.

In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the Arimidex group.

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

Clinical Trials Experience

Adjuvant Therapy

Adverse reaction data for adjuvant therapy are based on the ATAC trial [seeClinical Studies (14.1)]. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving Arimidex 1 mg and tamoxifen 20 mg, respectively.

Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.

Table 1 Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment in the ATAC trial *

Body system and adverse reactions by COSTART†‡	Arimidex 1 mg (N§ = 3092)	Tamoxifen 20 mg (N§ = 3094)
* The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. † COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. ‡ A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. § N=Number of patients receiving the treatment. ¶ Vaginal Hemorrhage without further diagnosis.
Body as a whole
Asthenia	575 (19)	544 (18)
Pain	533 (17)	485 (16)
Back pain	321 (10)	309 (10)
Headache	314 (10)	249    (8)
Abdominal pain	271    (9)	276    (9)
Infection	285    (9)	276    (9)
Accidental injury	311 (10)	303 (10)
Flu syndrome	175    (6)	195    (6)
Chest pain	200    (7)	150    (5)
Neoplasm	162    (5)	144    (5)
Cyst	138    (5)	162    (5)
Cardiovascular
Vasodilatation	1104 (36)	1264 (41)
Hypertension	402 (13)	349 (11)
Digestive
Nausea	343 (11)	335 (11)
Constipation	249 (8)	252 (8)
Diarrhea	265    (9)	216    (7)
Dyspepsia	206    (7)	169    (6)
Gastrointestinal disorder	210    (7)	158    (5)
Hemic and lymphatic
Lymphedema	304 (10)	341 (11)
Anemia	113    (4)	159    (5)
Metabolic and nutritional
Peripheral edema	311 (10)	343 (11)
Weight gain	285    (9)	274    (9)
Hypercholesterolemia	278    (9)	108 (3.5)
Musculoskeletal
Arthritis	512 (17)	445 (14)
Arthralgia	467 (15)	344 (11)
Osteoporosis	325 (11)	226    (7)
Fracture	315 (10)	209    (7)
Bone pain	201    (7)	185    (6)
Arthrosis	207    (7)	156    (5)
Joint Disorder	184    (6)	160    (5)
Myalgia	179    (6)	160    (5)
Nervous system
Depression	413 (13)	382 (12)
Insomnia	309 (10)	281    (9)
Dizziness	236    (8)	234    (8)
Anxiety	195    (6)	180    (6)
Paresthesia	215    (7)	145    (5)
Respiratory
Pharyngitis	443 (14)	422 (14)
Cough increased	261    (8)	287    (9)
Dyspnea	234    (8)	237    (8)
Sinusitis	184    (6)	159    (5)
Bronchitis	167    (5)	153    (5)
Skin and appendages
Rash	333 (11)	387 (13)
Sweating	145    (5)	177    (6)
Special Senses
Cataract Specified	182    (6)	213    (7)
Urogenital
Leukorrhea	86    (3)	286   (9)
Urinary tract infection	244   (8)	313 (10)
Breast pain	251    (8)	169    (6)
Breast Neoplasm	164    (5)	139    (5)
Vulvovaginitis	194   (6)	150    (5)
Vaginal Hemorrhage¶	122    (4)	180    (6)
Vaginitis	125    (4)	158    (5)

Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).

Table 2 Number of Patients with Pre-specified Adverse Reactions in ATAC Trial*

	Arimidex N=3092 (%)	Tamoxifen N=3094 (%)	Odds-ratio	95% CI
* Patients with multiple events in the same category are counted only once in that category. † Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. ‡ Percentages calculated based upon the numbers of patients with an intact uterus at baseline
Hot Flashes	1104 (36)	1264 (41)	0.80	0.73 − 0.89
Musculoskeletal Events†	1100 (36)	911 (29)	1.32	1.19 − 1.47
Fatigue/Asthenia	575 (19)	544 (18)	1.07	0.94 − 1.22
Mood Disturbances	597 (19)	554 (18)	1.10	0.97 − 1.25
Nausea and Vomiting	393 (13)	384 (12)	1.03	0.88 − 1.19
All Fractures	315 (10)	209   (7)	1.57	1.30 − 1.88
Fractures of Spine, Hip, or Wrist	133   (4)	91   (3)	1.48	1.13 − 1.95
Wrist/Colles’ fractures	67   (2)	50   (2)
Spine fractures	43   (1)	22   (1)
Hip fractures	28   (1)	26   (1)
Cataracts	182   (6)	213   (7)	0.85	0.69 − 1.04
Vaginal Bleeding	167   (5)	317 (10)	0.50	0.41 − 0.61
Ischemic Cardiovascular Disease	127   (4)	104   (3)	1.23	0.95 − 1.60
Vaginal Discharge	109   (4)	408 (13)	0.24	0.19 − 0.30
Venous Thromboembolic events	87   (3)	140   (5)	0.61	0.47 − 0.80
Deep Venous Thromboembolic Events	48   (2)	74   (2)	0.64	0.45 − 0.93
Ischemic Cerebrovascular Event	62   (2)	88   (3)	0.70	0.50 − 0.97
Endometrial Cancer‡	4 (0.2)	13 (0.6)	0.31	0.10 − 0.94

Ischemic Cardiovascular Events

Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% Arimidex vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the Arimidex arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the Arimidex arm and 34/3094 (1.1%) patients in the tamoxifen arm.

In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on Arimidex and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving Arimidex and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving Arimidex and 8/249 (3.2%) patients receiving tamoxifen.

Bone Mineral Density Findings

Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving Arimidex had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.

Because Arimidex lowers circulating estrogen levels it may cause a reduction in bone mineral density.

A post-marketing trial assessed the combined effects of Arimidex and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture.

Postmenopausal women with early breast cancer scheduled to be treated with Arimidex should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.

Cholesterol

During the ATAC trial, more patients receiving Arimidex were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).

A post-marketing trial also evaluated any potential effects of Arimidex on lipid profile. In the primary analysis population for lipids (Arimidex alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.

In secondary population for lipids (Arimidex+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.

In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.

In this trial, treatment for 12 months with Arimidex alone had a neutral effect on lipid profile. Combination treatment with Arimidex and risedronate also had a neutral effect on lipid profile.

The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with Arimidex should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.

Other Adverse Reactions

Patients receiving Arimidex had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving Arimidex had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)].

Patients receiving Arimidex had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].

Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the Arimidex-treated patients 317 (10%) versus 167 (5%), respectively.

Patients receiving Arimidex had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.

10-year median follow-up Safety Results from the ATAC Trial

Results are consistent with the previous analyses.

Serious adverse reactions were similar between Arimidex (50%) and tamoxifen (51%).

• Cardiovascular events were consistent with the known safety profiles of Arimidex and tamoxifen. • The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the Arimidex group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period. • The cumulative incidence of new primary cancers was similar in the Arimidex group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the Arimidex group (0.2%). • The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the Arimidex treatment group. First-Line Therapy

Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.

Table 3 – Adverse Reactions Occurring with an Incidence of at Least 5% in Trials 0030 and 0027

Body system Adverse Reaction*	Number (%) of subjects
	Arimidex (N=506)	Tamoxifen (N=511)
* A patient may have had more than 1 adverse event.
Whole body
Asthenia	83 (16)	81 (16)
Pain	70 (14)	73 (14)
Back pain	60 (12)	68 (13)
Headache	47   (9)	40   (8)
Abdominal pain	40   (8)	38   (7)
Chest pain	37   (7)	37   (7)
Flu syndrome	35   (7)	30   (6)
Pelvic pain	23   (5)	30   (6)
Cardiovascular
Vasodilation	128 (25)	106 (21)
Hypertension	25   (5)	36   (7)
Digestive
Nausea	94 (19)	106 (21)
Constipation	47   (9)	66 (13)
Diarrhea	40   (8)	33   (6)
Vomiting	38   (8)	36   (7)
Anorexia	26   (5)	46   (9)
Metabolic and Nutritional
Peripheral edema	51 (10)	41   (8)
Musculoskeletal
Bone pain	54  (11)	52 (10)
Nervous
Dizziness	30   (6)	22   (4)
Insomnia	30   (6)	38   (7)
Depression	23   (5)	32   (6)
Hypertonia	16   (3)	26   (5)
Respiratory
Cough increased	55 (11)	52 (10)
Dyspnea	51 (10)	47   (9)
Pharyngitis	49 (10)	68 (13)
Skin and appendages
Rash	38   (8)	34   (8)
Urogenital
Leukorrhea	9   (2)	31   (6)

Less frequent adverse experiences reported in patients receiving Arimidex 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.

Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.

Table 4 – Number of Patients with Pre-specified Adverse Reactions in Trials 0030 and 0027

	Number (n) and Percentage of Patients
Adverse Reaction*	Arimidex 1 mg (N=506) n (%)	NOLVADEX 20 mg (N=511) n (%)
* A patient may have had more than 1 adverse reaction. † Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡ Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.
Depression	23   (5)	32   (6)
Tumor Flare	15   (3)	18   (4)
Thromboembolic Disease†	18   (4)	33   (6)
Venous†	5	15
Coronary and Cerebral‡	13	19
Gastrointestinal Disturbance	170 (34)	196 (38)
Hot Flushes	134 (26)	118 (23)
Vaginal Dryness	9   (2)	3   (1)
Lethargy	6   (1)	15   (3)
Vaginal Bleeding	5   (1)	11   (2)
Weight Gain	11   (2)	8   (2)

Second-Line Therapy

Arimidex was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the Arimidex-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction.

The principal adverse reaction more common with Arimidex than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:

Table 5 – Number (N) and Percentage of Patients with Adverse Reactions in Trials 0004 and 0005

Adverse Reaction*	Arimidex		Arimidex		Megestrol Acetate
	1 mg		10 mg		160 mg
	(N=262)		(N=246)		(N=253)
	n	%	n	%	n	%
* A patient may have had more than one adverse reaction.
Asthenia	42	(16)	33	(13)	47	(19)
Nausea	41	(16)	48	(20)	28	(11)
Headache	34	(13)	44	(18)	24	(9)
Hot Flashes	32	(12)	29	(11)	21	(8)
Pain	28	(11)	38	(15)	29	(11)
Back Pain	28	(11)	26	(11)	19	(8)
Dyspnea	24	(9)	27	(11)	53	(21)
Vomiting	24	(9)	26	(11)	16	(6)
Cough Increased	22	(8)	18	(7)	19	(8)
Diarrhea	22	(8)	18	(7)	7	(3)
Constipation	18	(7)	18	(7)	21	(8)
Abdominal Pain	18	(7)	14	(6)	18	(7)
Anorexia	18	(7)	19	(8)	11	(4)
Bone Pain	17	(6)	26	(12)	19	(8)
Pharyngitis	16	(6)	23	(9)	15	(6)
Dizziness	16	(6)	12	(5)	15	(6)
Rash	15	(6)	15	(6)	19	(8)
Dry Mouth	15	(6)	11	(4)	13	(5)
Peripheral Edema	14	(5)	21	(9)	28	(11)
Pelvic Pain	14	(5)	17	(7)	13	(5)
Depression	14	(5)	6	(2)	5	(2)
Chest Pain	13	(5)	18	(7)	13	(5)
Paresthesia	12	(5)	15	(6)	9	(4)
Vaginal Hemorrhage	6	(2)	4	(2)	13	(5)
Weight Gain	4	(2)	9	(4)	30	(12)
Sweating	4	(2)	3	(1)	16	(6)
Increased Appetite	0	(0)	1	(0)	13	(5)

Other less frequent (2% to 5%) adverse reactions reported in patients receiving Arimidex 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection

Cardiovascular: Hypertension; thrombophlebitis

Hepatic: Gamma GT increased; SGOT increased; SGPT increased

Hematologic: Anemia; leukopenia

Metabolic and Nutritional: Alkaline phosphatase increased; weight loss

Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving Arimidex. Increases in LDL cholesterol have been shown to contribute to these changes.

Musculoskeletal: Myalgia; arthralgia; pathological fracture

Nervous: Somnolence; confusion; insomnia; anxiety; nervousness

Respiratory: Sinusitis; bronchitis; rhinitis

Skin and Appendages:  Hair thinning (alopecia); pruritus

Urogenital: Urinary tract infection; breast pain

The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.

Table 6 Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005

	Arimidex		Arimidex		Megestrol Acetate
	1 mg		10 mg		160 mg
	(N=262)		(N=246)		(N=253)
Adverse Reaction Group	n	(%)	n	(%)	n	(%)
Gastrointestinal Disturbance	77	(29)	81	(33)	54	(21)
Hot Flushes	33	(13)	29	(12)	35	(14)
Edema	19	(7)	28	(11)	35	(14)
Thromboembolic Disease	9	(3)	4	(2)	12	(5)
Vaginal Dryness	5	(2)	3	(1)	2	(1)
Weight Gain	4	(2)	10	(4)	30	(12)

Post-Marketing Experience

These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of Arimidex:

• Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis • Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome • Cases of allergic reactions including angioedema, urticaria and anaphylaxis [see Contraindications (4.2)] • Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)

Tamoxifen

Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of Arimidex and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.

Estrogen

Estrogen-containing therapies should not be used with Arimidex as they may diminish its pharmacological action.

Warfarin

In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.

Cytochrome P450

Based on in vitro and in vivo results, it is unlikely that co-administration of Arimidex 1 mg will affect other drugs as a result of inhibition of cytochrome P450 [see Clinical Pharmacology (12.3)].

Arimidex (anastrozole) tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is:

Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.

Each tablet contains as inactive ingredients: lactose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

Mechanism of Action

The growth of many cancers of the breast is stimulated or maintained by estrogens.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Anastrozole is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

Pharmacodynamics

Effect on Estradiol

Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of Arimidex in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, Arimidex 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with Arimidex 1 mg.

The effect of Arimidex in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, Arimidex would not be expected to lower estradiol levels in premenopausal women.

Effect on Corticosteroids

In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.

Other Endocrine Effects

In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of Arimidex. Arimidex does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.

Pharmacokinetics

Absorption

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. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of anastrozole were similar in patients and healthy volunteers.

Distribution

Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of Arimidex. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range.

Metabolism

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 and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity.

Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

Excretion

Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours.

Effect of Gender and Age

Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.

Effect of Race

Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.

Effect of Renal Impairment

Anastrozole pharmacokinetics have been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment [see Dosage and Administration (2.1) and Use in Specific Populations (8.6)].

Effect of Hepatic Impairment

Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].

NDC 0310-0201-30

30 tablets

Arimidex®

anastrozole tablets

1 mg tablets

Rx only

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

Product of the United Kingdom

AstraZeneca

Arimidex  anastrozole tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0310-0201 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANASTROZOLE (ANASTROZOLE) ANASTROZOLE 1 mg

Inactive Ingredients Ingredient Name Strength LACTOSE, UNSPECIFIED FORM   MAGNESIUM STEARATE   HYPROMELLOSES   POLYETHYLENE GLYCOL 300   POVIDONES   SODIUM STARCH GLYCOLATE TYPE A POTATO   TITANIUM DIOXIDE

Product Characteristics Color WHITE Score no score Shape ROUND (logo consisting of a letter A (upper case) with an arrowhead attached to the foot of the extended right leg of the A) Size 6mm Flavor Imprint Code adx1 Contains

Packaging # Item Code Package Description 1 NDC:0310-0201-30 30 TABLET in 1 BOTTLE, PLASTIC 2 NDC:0310-0201-14 14 TABLET in 1 BOTTLE, PLASTIC 3 NDC:0310-0201-37 1 DOSE PACK in 1 BOX, UNIT-DOSE 3 30 TABLET in 1 DOSE PACK 4 NDC:0310-0201-97 6 DOSE PACK in 1 BOX, UNIT-DOSE 4 14 TABLET in 1 DOSE PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020541 01/16/1996

Labeler - AstraZeneca Pharmaceuticals LP (054743190)

Registrant - AstraZeneca PLC (230790719)

Revised: 05/2014   AstraZeneca Pharmaceuticals LP

Do not use Arimidex if you are pregnant. It could harm the unborn baby.

Arimidex may not work as well if you take it together with estrogen medication (such as hormone replacement therapy, estrogen creams, or birth control pills, injections, implants, skin patches, and vaginal rings).

Arimidex may increase your risk of a stroke or blood clot. Call your doctor at once if you have sudden numbness or weakness, (especially on one side of the body), sudden severe headache, slurred speech, or problems with vision or balance.

You should not use Arimidex if you are allergic to anastrozole, if you are breast-feeding a baby, or if you have not yet completed menopause. Arimidex is not for use in men or children.

To make sure Arimidex is safe for you, tell your doctor if you have:

• heart disease;

• circulation problems;

• a history of stroke or blood clot;

• severe liver disease;

• high cholesterol; or

• osteoporosis or low bone mineral density.

Arimidex can decrease bone mineral density, which may increase your risk of developing osteoporosis. Your bone mineral density may need to be tested before and during treatment with anastrozole.

Although it is not likely that a postmenopausal woman would be pregnant, anastrozole could harm an unborn baby. Do not take this medicine if you are pregnant or may become pregnant. Use effective birth control if you are not past menopause, and tell your doctor right away if you become pregnant during treatment.

It is not known whether anastrozole passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using Arimidex.

You may need to take a pregnancy test before using Arimidex, to make sure you are not pregnant.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Applies to anastrozole: oral tablet

Along with its needed effects, anastrozole (the active ingredient contained in Arimidex) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking anastrozole:

More common

• Blurred vision
• chest pain or discomfort
• dizziness
• headache
• nervousness
• pounding in the ears
• shortness of breath
• slow or fast heartbeat
• swelling of the feet or lower legs

Less common

• Arm, back, or jaw pain
• chest tightness or heaviness
• cough or hoarseness
• difficult or painful urination
• dizziness, severe
• fever or chills
• headache, continuing
• increased blood pressure
• lower back or side pain
• nausea
• pain, tenderness, bluish color, or swelling of the foot or leg
• sore throat
• sudden shortness of breath
• sweating
• unusual tiredness or weakness
• vaginal bleeding (unexpected and heavy)

Incidence not known

• Blistering, peeling, or loosening of the skin
• hives
• itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• red skin lesions, often with a purple center
• sores, ulcers, or white spots in the mouth or on the lips
• welts

Some side effects of anastrozole may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Acid or sour stomach
• back pain
• belching
• body aches or pain
• bone pain
• congestion
• constipation
• decrease in height
• diarrhea
• dry mouth
• dryness or soreness of the throat
• feeling of warmth
• fever
• flushing or redness of the skin, especially on the face and neck
• heartburn
• hot flashes
• increased appetite
• indigestion
• lack or loss of strength
• loss of appetite
• mood or mental changes
• pain in the back, ribs, arms, or legs
• pain, general
• pelvic pain
• runny nose
• skin rash
• stomach discomfort, upset, or pain
• tender, swollen glands in the neck
• trouble in swallowing
• voice changes
• vomiting
• weakness
• weight loss

Less common

• Anxiety and confusion
• breast pain
• chills
• cough producing mucus
• difficulty breathing
• dryness of the vagina
• general feeling of discomfort or illness
• itching of the skin
• joint pain and stiffness
• loss of hair
• muscle pain
• numbness or tingling of the hands or feet
• shivering
• sleepiness or unusual drowsiness
• trouble sleeping or sleeplessness
• weight gain
• wheezing