Anastrozole

14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer

Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of anastrozole tablets once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety.

Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.

	Number (%) of subjects
Receptor status	Trial 0030		Trial 0027
	AnastrozoleTablets 1 mg (n=171)	Tamoxifen 20 mg (n=182)	AnastrozoleTablets 1 mg (n=340)	Tamoxifen 20 mg (n=328)
ERER=Estrogen receptor and/or PgRPgR=Progesterone receptor	151 (88.3)	162 (89)	154 (45.3)	144 (43.9)
ERER=Estrogen receptor unknown, PgRPgR=Progesterone receptor Unknown	19 (11.1)	20 (11)	185 (54.4)	183 (55.8)

For the primary endpoints, trial 0030 showed that anastrozolehad a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for anastrozoleand tamoxifen. Trial 0027 showed that anastrozoleand tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 12 and Figures 5 and 6)

Endpoint	Trial 0030		Trial 0027
	AnastrozoleTablets 1 mg (N=171)	Tamoxifen 20 mg (N=182)	AnastrozoleTablets 1 mg (N=340)	Tamoxifen   20 mg (N=328)
Time to progression (TTP)
Median TTP (months)	11.1	5.6	8.2	8.3
Number (%) of subjects Who progressed	114 (67%)	138 (76%)	249 (73%)	247 (75%)
Hazard ratio (LCLLCL=Lower Confidence Limit)Tamoxifen: Anastrozole Tablets	1.42 (1.15)		1.01 (0.87)
2-sided 95% CICI=Confidence Interval	(1.11, 1.82)		(0.85, 1.2)
p-valueTwo-sided Log Rank	0.006		0.92
Best objective response rate
Number (%) of subjects With CRCR=Complete Response + PRPR=Partial Response	36 (21.1%)	31 (17%)	112 (32.9%)	107 (32.6%)
Odds Ratio (LCLLCL=Lower Confidence Limit)Anastrozole Tablets: Tamoxifen	1.3 (0.83)		1.01 (0.77)

Figure 5 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030

 Figure 6 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027

14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy

      Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to anastrozole. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.

      Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.

Table 13– Efficacy Results of Second-line Treatment

	Anastrozole Tablets 1 mg	AnastrozoleTablets 10 mg	Megestrol Acetate 160 mg
Trial 0004
(N. America)	(N=128)	(N=130)	(N=128)
Median Follow-up (months)Surviving Patients	31.3	30.9	32.9
Median Time to Death (months)	29.6	25.7	26.7
2 Year Survival Probability (%)	62	58	53.1
Median Time to Progression (months)	5.7	5.3	5.1
Objective Response (all patients) (%)	12.5	10.0	10.2
Stable Disease for >24 weeks (%)	35.2	29.2	32.8
Progression (%)	86.7	85.4	90.6
Trial 0005
(Europe, Australia, S. Africa)	(N=135)	(N=118)	(N=125)
Median Follow-up (months)Surviving Patients	31	30.9	31.5
Median Time to Death (months)	24.3	24.8	19.8
2 Year Survival Probability (%)	50.5	50.9	39.1
Median Time to Progression (months)	4.4	5.3	3.9
Objective Response (all patients) (%)	12.6	15.3	14.4
Stable Disease for >24 weeks (%)	24.4	25.4	23.2
Progression (%)	91.9	89.8	92

Table 14 – Pooled Efficacy Results of Second-line Treatment

16 HOW SUPPLIED/STORAGE AND HANDLING

Anastrozole Tablets is supplied as follows:

Product                                   NDC

No.                                          No.                              Strength

129030                                    63323-129-30                              1 mg                 30 tablets per bottle.

Storage

Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy

17.2 Allergic (Hypersensitivity) Reactions

      Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to immediately report this to their doctor.

17.3 Ischemic Cardiovascular Events

17.4 Bone Effects

      Patients should be informed that anastrozole tablets lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.

17.5 Cholesterol

17.6 Tamoxifen

ANASTROZOLE TABLETS

Read the information that comes with anastrozole tablets before you start taking it and each time you get a refill. The information may have changed. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Talk with your doctor about anastrozole tablets when you start taking it and at regular checkups.

What is anastrozole tablets?

Anastrozole tablets is a prescription medicine used in women who have finished menopause (“the change of life”) for:

• treatment of early breast cancer
  • after surgery, with or without radiation 
  • in women whose breast cancer is hormone receptor-positive
• first treatment of locally advanced or metastatic breast cancer, in women whose breast cancer is hormone receptor-positive or the hormone receptors are not known.
• treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy.

Anastrozole tablets do not work in women with breast cancer who have not finished menopause (premenopausal women).

Who should not take anastrozole tablets?

      Do not take anastrozole tablets if you:

• are pregnant, think you may be pregnant, or plan to get pregnant. Anastrozole tablets may harm your unborn child. If you become pregnant while taking anastrozole tablets, tell your doctor right away.
• have not finished menopause (are premenopausal).
• are allergic to any of the ingredients in anastrozole tablets. See the end of this leaflet for a list of the ingredients in anastrozole tablets.
• are a man or child.

What is the most important information I should know about anastrozole tablets?

Anastrozole tablets may cause serious side effects including:

• Heart disease. Women with early breast cancer, who have a history of blockages in heart arteries (ischemic heart disease) and who take anastrozole tablets may have a slight increase in this type of heart disease compared to similar patients who take tamoxifen.
  • Stop taking anastrozole tablets and call your doctor right away if you have chest pain or shortness of breath. These can be symptoms of heart disease.
• Osteoporosis (bone softening and weakening). Anastrozole tablets lowers estrogen in your body, which may cause your bones to become softer and weaker. This can increase your chance of fractures, specifically of the spine, hip and wrist. Your doctor may order a test for you called a bone mineral density study before you start taking anastrozole tablets and during treatment with anastrozole tablets as needed.

What should I tell my doctor before taking anastrozole tablets?

Anastrozole tablets may not be right for you. Before taking anastrozole tablets, tell your doctor about all your medical conditions, including if you:

• have not finished menopause. Talk to your doctor if you are not sure. See “Who should not take anastrozole tablets?”
• have had a previous heart problem
• have a condition called osteoporosis
• have high cholesterol
• are pregnant, planning to become pregnant, or breast feeding. See “Who should not take anastrozole tablets?”
• are nursing a baby. It is not known if anastrozole passes into breast milk. You and your doctor should decide if you will take anastrozole tablets or breast feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• Tamoxifen. You should not take anastrozole tablets with tamoxifen. Taking tamoxifen with anastrozole tablets may lower the amount of anastrozole in your blood and may cause anastrozole not to work as well.
• Medicines containing estrogen. Anastrozole tablets may not work if taken with one of these medicines: 
  • hormone replacement therapy 
  • birth control pills 
  • estrogen creams 
  • vaginal rings 
  • vaginal suppositories

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take anastrozole tablets?

• Take anastrozole tablets exactly as prescribed by your doctor.
• Keep taking anastrozole tablets for as along as your doctor prescribes it for you.
• Take one anastrozole tablet each day.
• Anastrozole tablets can be taken with or without food.
• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
• If you have taken more anastrozole tablets than your doctor has prescribed, contact your doctor right away. Do not take any additional anastrozole tablets until instructed to do so by your doctor.

Talk with your doctor about any health changes you have while taking anastrozole tablets.

What are possible side effects of anastrozole tablets?

Anastrozole tablets can cause serious side effects including:

• See “What is the most important information I should know about Anastrozole tablets?”.
• increased blood cholesterol (fat in the blood). Your doctor may check your cholesterol while you take anastrozole tablets therapy.
• skin reactions. Stop taking anastrozole tablets and call your doctor right away if you get any skin lesions, ulcers, or blisters.
• severe allergic reactions. Get medical help right away if you have: 
  • swelling of the face, lips, tongue, or throat. 
  • trouble swallowing 
  • trouble breathing
• liver problems. Anastrozole tablets can cause inflammation of the liver and changes in blood tests of the liver function. Your doctor may monitor you for this. Stop taking anastrozole tablets and call your doctor right away if you have any of these signs or symptoms of a liver problem:
  • a general feeling of not being well
  • yellowing of the skin or whites of the eyes
  • pain on the right side of your abdomen  

Common side effects in women taking anastrozole tablets include:

• hot flashes
• weakness
• joint pain
• carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand)
• pain
• sore throat
• mood changes
• high blood pressure
• depression
• nausea and vomiting
• thinning of the hair (hair loss)
• rash
• back pain
• sleep problems
• bone pain
• headache
• swelling
• increased cough
• shortness of breath
• lymphedema (build up of lymph fluid in the tissues of your affected arm)
• trigger finger (a condition in which one of your fingers or your thumb catches in a bent position)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

HOW SHOULD I STORE ANASTROZOLE TABLETS?

• Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
• Keep anastrozole tablets and all medicines out of the reach of children.

General information about anastrozole tablets.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take anastrozole tablets for a condition for which it was not prescribed. Do not give anastrozole tablets to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about anastrozole tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about anastrozole tablets that is written for health professionals.

What are the ingredients in anastrozole tablet?

Active ingredient: anastrozole

Inactive ingredients: lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate and opadry white (methylhydroxypropyl cellulose, polyethylene glycol and titanium dioxide).

Manufactured for:

APP Pharmaceuticals, LLC

Schaumburg, IL 60173

Made in India

For Product Inquiry:

Anastrozole Tablets 1 mg Container Label

NDC 63323-129-30

129030

ANASTROZOLE

TABLETS

1 mg

Rx only

30 Tablets