Anastrozole - Indications, Contraindications, Mechanism of Action, and Side Effects

Overview

Anastrozole is an aromatase inhibitor. It is marketed by AstraZeneca and was approved by the Food and Drug Administration (FDA) for the treatment of breast cancer in postmenopausal women in 1995.

Anastrozole inhibits the enzyme aromatase that converts androgens to estrogen, thereby reducing the estrogen levels in the body. Estrogens are responsible for the stimulation of breast cancer growth, meaning that a reduction in estrogen levels contributes to less stimulation and maintenance of breast cancer growth.

How Does Anastrozole Work?

Breast cancer growth may often depend on the stimulatory and maintenance effect of estrogens to grow.

Adrenal androgens (mainly androstenedione and testosterone) are converted to estrone and estradiol (estrogens) by the aromatase enzyme in postmenopausal women. The inhibition of the aromatase enzyme would, therefore, potentially cause the suppression of estrogen synthesis, which would, in turn, contribute to lowering the possibility of breast cancer growth. The drug Anastrozole is a selective, non-steroidal aromatase inhibitor. That means that it can lower estrogen levels by inhibiting the enzyme aromatase, thereby helping with the treatment of breast cancer.

Uses of Anastrozole

Anastrozole is indicated for the following:

• Hormone receptor-positive early breast cancer in postmenopausal women, as an adjuvant treatment.

• As a first-line treatment in hormone receptor-positive or hormone receptor unknown breast cancer in postmenopausal women (locally advanced or metastatic).

• Advanced breast cancer in postmenopausal women who display the progression of disease after treatment with Tamoxifen.

Limitations-

Patients who have not responded to Tamoxifen are rarely likely to show any changes upon administration of Anastrozole.

Dosage Restrictions

1. Route of Administration- Oral.

2. Dosage Strengths-

• 1 mg tablet.

3. Dosage Forms-

• White, biconvex, film-coated tablets debossed with a logo on one side and the tablet strength marked Adx 1 on the other side.

The recommended dosage is one 1 mg tablet taken once daily.

Special Considerations

• Pregnancy- Anastrozole can cause fetal harm if administered to pregnant women. As such, it does not benefit premenopausal women, so the use of Anastrozole in pregnant women is not encouraged.

• Lactation- No data is available on whether Anastrozole can be excreted in human milk, but there is a possibility. Depending on individual needs and dependency on the drug, there may be a need to choose between discontinuing breastfeeding or discontinuing the drug.

• Pediatric Patients- Trials performed on young boys with gynecomastia and young girls with McCune-Albright syndrome or precocious puberty have demonstrated no particularly significant outcome.

• Geriatric Patients- The efficacy of Anastrozole has reportedly been better in patients over 65 years of age.

• Renal Impairment- No dosage adjustment is necessary.

• Hepatic Impairment- No dosage adjustment is necessary for patients with stable hepatic cirrhosis, while the effects of the drug on those with severe hepatic impairment are unknown.

Warnings and Contraindications

Contraindications

Anastrozole is contraindicated in the following cases:

• Premenopausal Women- No benefits have been noted in premenopausal women, so its use is contraindicated in them.

• Pregnancy- Anastrozole has not been studied in controlled trials among pregnant women, and there is a potential for causing harm to the fetus. Women who are pregnant or become pregnant while taking the drug should be advised of the possible harm to the fetus and preferably avoid taking the drug.

• Hypersensitivity- Anastrozole is contraindicated in anyone who has a hypersensitivity towards the drug or other constituents of the formulation.

Warnings and Precautions

• Cholesterol Levels- Patients receiving Anastrozole are more likely to experience an elevation in serum cholesterol than patients receiving Tamoxifen.

• Ischemic Cardiovascular Events- Patients with pre-existing ischemic heart disease may display an increased incidence of ischemic cardiovascular events when compared to Tamoxifen.

• Bone Effects- The lumbar spine and total hip bone mineral density tend to decrease compared to the baseline in patients receiving Anastrozole.

For Patients

What Is HER2-Positive Breast Cancer?

Breast cancers that test positive for the HER2 protein are called HER2-positive breast cancers. HER2 (human epidermal growth factor receptor 2) is a protein capable of causing cancer cell growth. HER2-positive breast cancer can be aggressive in comparison to other types of breast cancers.

Why Is Anastrozole Prescribed for Breast Cancer?

Anastrozole is an aromatase inhibitor. Aromatase is responsible for the production of estrogens, so its inhibition can result in a reduction in the estrogen levels that contribute to the growth of breast cancer. Anastrozole is a hormone type of treatment, so it is typically prescribed for postmenopausal women with hormone-dependent breast cancer.

Facts You Should Know About Anastrozole

• Anastrozole is available in tablet form at a dosage of 1 mg. It is to be taken at a dosage of one 1 mg tablet once daily.

• While Anastrozole is usually prescribed for treatment, it has been known to help with the prevention of breast cancer in at-risk women.

How Should You Take Anastrozole?

• Anastrozole is available as a 1 mg tablet for oral consumption once daily.

• It can be taken with or without food.

• The drug needs to be taken around the same time every day.

• The dosage should not be increased or decreased.

• Anastrozole is meant for long-term use. If you respond better after taking Anastrozole, do not stop taking the drug of your own accord. Continue taking the drug until your healthcare provider asks you to stop. This may take several years.

• In case of side effects, inform your doctor. Do not stop taking the drug yourself.

What Should You Discuss With Your Doctor Before Beginning Anastrozole Therapy?

• Allergies- Make it a point to check the ingredient list of Anastrozole tablets and inform your physician if you are allergic to Anastrozole or any of the other ingredients in the formulation.

• Medical History- Inform your doctor of any concurrent illnesses you may be suffering from, especially osteoporosis, high cholesterol levels, or previous heart conditions.

• Drug History- Give your doctor a complete list of the prescription and non-prescription medications you may be taking, including any herbal supplements, nutritional supplements, and vitamins. Make sure that you inform your doctor if you are already taking Tamoxifen as the use of both drugs in combination is contraindicated, and if you are taking any form of estrogen-containing medication like birth control pills, estrogen creams, or hormone replacement therapy.

• Pregnancy- If you are pregnant or planning to get pregnant any time soon, tell your doctor. Anastrozole may harm the fetus. If you get pregnant while on Anastrozole, inform your doctor as soon as you find out.

• Lactation- Let your doctor know if you are breastfeeding. The possibility of Anastrozole passing into the breastmilk is unknown, so it is best to avoid either one. You and your physician must consider all your needs and available options before deciding whether to avoid breastfeeding or stop taking Anastrozole.

• Menopause- Inform your doctor if you have yet to attain menopause. The use of Anastrozole is not recommended in premenopausal women as it provides no beneficial effects.

Is Anastrozole Safe?

Anastrozole is quite safe to take in the long term. However, it does come with its own challenges. This drug causes a reduction in estrogen levels in order to stop or slow the growth of breast cancer cells that require estrogen to grow. A reduction in estrogen levels over a long period of time may result in the weakening of bones and increase their susceptibility to breakage. Scheduled bone density scans, treatment with Bisphosphonate, and instructions on exercises and diet for better bone strength may all help with combating this side effect.

Is Anastrozole Effective?

• Anastrozole is quite effective in terms of long-term survival benefits.

• One study showed that the drug displayed clinical benefits in 59 % of patients compared to 46 % of patients on Tamoxifen.

• On the whole, Anastrozole has displayed superior efficacy to Tamoxifen, with a significant increase in the time to progression (TTP) of the disease, while also having a lower incidence of side effects like thromboembolic events and vaginal bleeding than Tamoxifen.

What Side Effects Can You Expect With Anastrozole?

The common side effects that occur with the use of Anastrozole are as follows:

• Nausea.

• Vomiting.

• Joint pain.

• Hot flashes.

• General weakness and pain.

• Back pain.

• Bone pain.

• Carpal tunnel syndrome (pain, weakness, tingling, and cold sensations in the hands).

• Headache.

• Shortness of breath.

• Sore throat.

• Cough.

• Lymphedema (lymphatic fluid buildup in the affected arm tissues).

• Thinning of the hair.

• Rashes.

• Mood swings.

• Depression.

• Hypertension (high blood pressure).

• Issues with sleep.

• Trigger finger (a catch in the fingers or thumb while in a bent position).

The more serious side effects that can be expected include:

• Increase in blood cholesterol levels.

• Severe hypersensitivity or allergic reactions.

• Skin reactions like ulcers, blisters, and other lesions.

• Liver issues like inflammation of the liver. Symptoms that may indicate liver trouble in patients include yellowing of the skin and eye whites, feeling unwell, and experiencing pain on the right side of the abdomen.

Can You Stop Taking Anastrozole Without the Approval of Your Doctor?

• Never stop taking Anastrozole without approval from your doctor. Consult your physician or visit the emergency room if you experience any side effects that require immediate attention.

• Remember that you must continue taking Anastrozole regardless of how well you respond to it unless your doctor explicitly mentions otherwise. The drug is meant for long-term use and should not be stopped even if you respond well to it.

Are There Any Dietary Restrictions to Consider When Taking Anastrozole?

You may continue to follow your regular diet unless your doctor asks you to change it. No dietary restrictions are needed.

How Should You Store Anastrozole?

• Store Anastrozole at a temperature between 68 degrees Fahrenheit and 77 degrees Fahrenheit or 20 degrees Celsius and 25 degrees Celsius.

• Anastrozole tablets should be stored in the original packaging or container with the lid tightly closed.

• Keep this drug far from the reach of children and pets.

How Should You Dispose of Anastrozole?

• Anastrozole should not be disposed of by flushing or throwing it out with regular garbage.

• Dispose of Anastrozole through your local medicine take-back program, which you can access or learn more about through your local pharmacist.

• If you do not have access to a medicine take-back program, ask your local pharmacist about any other drug disposal options available to you.

What To Do in Case of Overdose?

• If you overdose on Anastrozole, contact your doctor immediately, and do not take another tablet until your doctor tells you to do so.

• If you experience severe side effects like seizures or breathing difficulty, a bystander or family member should take you to the emergency room or contact local poison control services.

For Doctors

Indications-

Anastrozole is indicated for the following purposes:

• Hormone receptor-positive early breast cancer in postmenopausal women, as an adjuvant treatment.

• As a first-line treatment in hormone receptor-positive or hormone receptor unknown breast cancer in postmenopausal women (locally advanced or metastatic).

• Advanced breast cancer in postmenopausal women who display the progression of disease after treatment with Tamoxifen.

What Is the Pharmacology of Anastrozole?

Description-

Anastrozole is an aromatase inhibitor with the molecular formula C17H19N5 and a molecular weight of 293.4.

Components-

1. Active Ingredients-

• Anastrozole.

2. Inactive Ingredients-

• Lactose.

• Magnesium stearate.

• Hydroxypropylmethylcellulose.

• Polyethylene glycol.

• Povidone.

• Sodium starch glycolate.

• Titanium dioxide.

Clinical Pharmacology

Mechanism of Action-

Breast cancer cells often require the stimulatory and maintenance effect of estrogens to grow. The aromatase enzyme in postmenopausal women can cause the conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol (estrogens). Inhibiting the aromatase enzyme would help to suppress estrogen synthesis, thereby limiting the possibility of breast cancer growth. The drug Anastrozole is a selective, non-steroidal aromatase inhibitor that can lower estrogen levels by inhibiting the enzyme aromatase and thus help with the treatment of breast cancer.

Pharmacodynamics-

• Estradiol- 1 mg of Anastrozole can suppress estradiol by 70 % within 24 hours and 80 % within 14 days of daily dosing.

• Corticosteroids- Glucocorticoid and mineralocorticoid replacements are not required when using Anastrozole. It does not affect corticosteroid synthesis or secretion.

• Thyroid Stimulating Hormone (TSH)- Anastrozole does not cause an increase in the TSH levels.

Pharmacokinetics-

• Mean Cmax- Decreased by 16 %.

• Median Tmax- Delayed from 2 to 5 hours upon administration of Anastrozole 30 minutes after food.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

• Pharmacokinetic Changes- Linear over 1 to 20 mg dose range. No change with repeated dosing.

A. Distribution-

• Steady-state Plasma Levels- 3- to 4-fold higher than levels after a single dose of Anastrozole.

• Time to Approach Steady-state Levels- Within seven days of once-daily dosing.

• Binding to Plasma Proteins- 40 %.

B. Metabolism-

• Metabolic Processes- N-dealkylation, hydroxylation, and glucuronidation.

• Anastrozole inhibited cytochrome P450 1A2, 2C8/9, and 3A4-catalyzed reactions.

• No inhibition of reactions catalyzed by cytochrome P450 2A6 or 2D6.

C. Excretion-

• Recovery of Anastrozole- 85 % recovered in feces and urine.

D. Elimination-

• 85 % is carried out by hepatic metabolism.

• 10 % is accounted for by renal elimination.

• Mean Elimination Halflife- 50 hours.

Special Considerations

• Renal Impairment- No dosage adjustment is necessary for patients with renal impairment.

• Hepatic Impairment- No dosage adjustment is necessary for patients with stable hepatic impairment, but the effect on patients with severe hepatic impairment is unknown.

• Age- No age-related effects have been reported in postmenopausal women below 50 years or over 80 years of age.

Drug Interactions-

• Tamoxifen- The plasma concentration of Anastrozole is reduced by 27 % upon coadministration with Tamoxifen. No efficacy has been noted corresponding to the combined use of these two drugs. Tamoxifen should not be administered alongside Anastrozole.

• Estrogen- Therapies containing estrogen are to be avoided to ensure that the pharmacological action is not compromised.

• Warfarin- The exposure and anticoagulant effects of R-Warfarin and S-Warfarin showed no differences upon administration of Anastrozole.

What Have Clinical Trials Shown With Regard to Anastrozole?

1. Adjuvant Treatment in Postmenopausal Women With Breast Cancer

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was a multicenter, double-blinded trial that randomized postmenopausal women suffering from operable breast cancer (n = 9366) to the following groups:

• Adjuvant treatment with Anastrozole 1 mg daily.

• Tamoxifen 20 mg daily.

• Combination of Anastrozole 1 mg daily and Tamoxifen 20 mg daily for five years or until disease recurrence.

Primary Endpoint-

• Disease-free survival.

Secondary Endpoints-

• Distant disease-free survival.

• Incidence of contralateral breast cancer.

• Overall survival.

Results-

Anastrozole and Tamoxifen demonstrated no efficacy benefits in comparison to Tamoxifen alone, so this arm of the trial was discontinued. Patients in the other two arms underwent treatment for a median of 60 months (5 years), with a median follow-up period of 68 months.

Disease-free survival in the intent-to-treat population for Anastrozole versus Tamoxifen was statistically significant [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127].

84 % of the trial patients belonged to the hormone receptor-positive subpopulation. These patients also demonstrated statistically significant disease-free survival (HR = 0.83, 95% CI: 0.73, 0.94, p=0.0049) in the Anastrozole group when compared with the Tamoxifen group.

2. First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women

Two clinical trials (Trial 0030 and Trial 0027) with similar designs were conducted to evaluate the efficacy of Anastrozole compared to Tamoxifen as first-line treatment in postmenopausal women for hormone receptor-positive or hormone receptor unknown breast cancer that may be locally advanced or metastatic. Both studies were double-blinded, controlled clinical studies. 1021 patients between 30 and 92 years of age were randomized to the following treatment arms:

• Anastrozole 1 mg once daily.

• Tamoxifen 20 mg once daily.

Primary Endpoints-

• Time to tumor progression.

• Objective tumor response rate.

• Safety.

Results-

• Both trials showed similar objective tumor response rates.

• The time to tumor progression for Anastrozole was significantly better than that of Tamoxifen (p=0.006) in Trial 0030.

• Trial 0027 showed a similar time to tumor progression for both groups.

3. Second-Line Therapy for Advanced Breast Cancer in Postmenopausal Women Who Experienced Disease Progression Following Tamoxifen Therapy

Two double-blinded (with respect to Anastrozole) controlled clinical trials (Trial 0004 and Trial 0005) were carried out among 375 postmenopausal women (each) with advanced breast cancer who displayed the progression of disease after treatment with Tamoxifen for advanced or early breast cancer.

Eligible patients were randomized to the following groups:

• A single daily dose of either 1 mg or 10 mg of Anastrozole.

• Megestrol acetate 40 mg four times daily.

Primary Endpoints-

• Time to progress.

• Objective response rates.

Other variables studied included-

• The rate of prolonged, stable disease (characterized as prolonged disease lasting over 24 weeks).

• Rate of progression.

• Survival.

Results-

Pooled data from the two trials suggested that the objective response rates and median times to progression and death were not different for patients randomized to either group. Additionally, Anastrozole 10 mg demonstrated no superiority compared to Anastrozole 1 mg.

Patient Counseling Information

Administration Instructions-

• Take Anastrozole only as prescribed by the doctor.

• This drug may be taken with or without food.

• Swallow these tablets whole and do not crush, split, or chew them.

Complications or Side Effects-

• Pregnancy- Patients should be warned of the possible ill effects on the fetus if they take Anastrozole during pregnancy. It is also not recommended in premenopausal women.

• Breastfeeding- As it is unknown whether the drug will pass into breast milk, patients should be advised to either stop breastfeeding or terminate the drug. Depending on individual needs and other relevant factors, this decision will rest on the doctor and patient.

• Hypersensitivity- Patients should be warned of the potential for severe allergic reactions, including swelling of the face, throat, tongue, and lips, as well as difficulty breathing or swallowing. They must immediately contact their physician if they experience such reactions.

• Cholesterol- Inform patients that cholesterol levels may increase when using Anastrozole.

• Bone Effects- The lowering of estrogen levels may cause a decrease in bone mineral density and, subsequently, bone strength. This can also increase the risk of fractures and osteoporosis.

• Ischemic Cardiovascular Events- Patients with a prior history of ischemic heart disease should be informed about the increased incidence of cardiovascular events among such patients and should be warned to be cautious.

• Tamoxifen- Advise patients to avoid taking Tamoxifen and Anastrozole together.