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

Overview

The aromatase inhibitor Anastrozole received approval from the Food and Drug Administration (FDA) for its therapeutic usage in breast cancer cases in postmenopausal women in the year 1995.

Anastrozole inhibits the aromatase enzyme, which converts androgens to estrogen, thereby reducing 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 Anastrozole Works?

Anastrozole basically works by reducing the production of estrogen. The stimulatory and maintenance effects of estrogen tend to influence breast cancer growth. The aromatase enzyme plays a critical role in estrogen synthesis in postmenopausal women. It is this aromatase enzyme that catalyzes the conversion of the adrenal androgens, mostly testosterone and androstenedione, into estrone and estradiol. There are two different types of estrogen.

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. That is why it is often advised as a potent breast cancer medication.

What Is Anastrozole Used For?

Anastrozole is used for treatment in the following scenarios:

• Early-stage breast cancers that are hormone receptor-positive in women who have already attained menopause (adjuvant therapy).

• 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 failed to respond properly to Tamoxifen therapy.

Though Anastrozole has a wide application in breast cancer patients, it is important to keep track of Anastrozole side effects that might develop during the treatment course.

Limitations

Patients who have not responded to Tamoxifen are unlikely to show any changes upon administration of Anastrozole for breast cancer.

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, Adx 1, marked on the other side.

The daily recommended dosage for Anastrozole tablet form is 1 mg.

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 are available on whether Anastrozole can be excreted in human milk; however, it is possible. 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 aged 65 years or older.

• Renal Impairment - No dosage adjustment is necessary.

• Hepatic Impairment - Patients with stable hepatic cirrhosis do not necessarily need Anastrozole dosage adjustments, 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 individuals with hypersensitivity to the drug or its other constituents.

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 - The risk of an ischemic cardiovascular event will be increased with Anastrozole. It is estimated to be more than the risk associated with Tamoxifen.

• Bone Effects - Lumbar spine and total hip bone mineral density tend to decrease from baseline in patients receiving Anastrozole.

For Patients

What is Anastrozole?

Anastrozole is an effective drug choice for certain breast cancers; to be more precise, it is used for treating HER2-positive breast cancers. It belongs to the aromatase inhibitors, which is an anticancer drug group that is often considered for the treatment of several cancers. Breast cancers that test positive for a specific bodily protein, the so-called HER2 protein, are categorized as HER2-positive breast cancers. Breast cancer growth in HER2-positive cases can be effectively controlled with Anastrozole treatment.

Why Is Anastrozole Prescribed?

Anastrozole is an aromatase inhibitor. Aromatase is the enzyme that is critically involved in estrogen production, so its inhibition can result in a reduction in the estrogen levels that contribute to the growth of breast cancer. Anastrozole is basically a hormonal treatment, so it is typically prescribed for postmenopausal women with hormone-dependent breast cancer. Although it can significantly reduce cancer growth, the long-term side effects of Anastrozole must be considered when used for a prolonged period.

Facts You Should Know About Anastrozole

• Anastrozole is available as a 1 mg tablet. It is to be taken as 1 mg 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 I Use Anastrozole?

Anastrozole is marketed in tablet form, so you have to take it orally.

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

• There is no specific time for the tablet intake, but stick to the same time throughout your therapy.

• You must stick to the dosage your doctor has suggested. Do not try to change the dose by yourself.

• 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.

• Do not club it with other medicines, as Anastrozole interacts with them, which could cause harm or even affect the drug’s effectiveness. So, to be on the safer side, get it checked with your doctor beforehand.

Administration Instructions

• Take Anastrozole at the dose your doctor has prescribed.

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

• You can take the tablet with or without food; it won't affect the medicine’s effectiveness.

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

• Allergies - Make it a point to check the ingredient list for Anastrozole tablets, and inform your physician if you are allergic to Anastrozole or any other ingredient 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 are taking. Make sure that you inform your doctor if you are already taking Tamoxifen, as the use of both drugs in combination is contraindicated, or 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 become pregnant 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 breastmilk is unknown, so it is best to avoid both. 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 not yet reached 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, even in the long term. However, it does come with its own challenges. This medicine brings out its action by bringing down the estrogen level, which is beneficial for HER2-positive cancers; however, it can have some negative implications as well.

A reduction in estrogen levels over a long period of time may result in the weakening of bones and increase their risk for fractures. Periodic bone density scans, treatment with a Bisphosphonate, and following instructions for exercise and diet to improve bone strength may all help combat this side effect.

If you are planning to consider Anastrozole for breast cancer, consult with an oncologist at iCliniq to evaluate whether it's the right choice.

What Anastrozole Precautions Should I Follow?

It is very important to follow certain precautions to ensure safety during Anastrozole therapy. Never miss follow-ups, and get yourself checked by the doctor so you can see how well the medicine is working for you. If the progress is not up to mark, your doctor might change the drug or suggest another treatment, so it is essential to monitor the disease's progress through periodic checkups.

Anastrozole uses aromatase inhibition to reduce the estrogen level, and therefore, it can cause harm if taken while you are pregnant. Though that is not really relevant in postmenopausal women, you should keep this in mind, and if you have any sort of confusion on whether you have attained menopause or not, get it cleared right away with the doctor, and then proceed with the therapy.

You are not supposed to take Anastrozole and Tamoxifen together, as they can bring in harmful interactions. Keep track of your bone density, as Anastrozole can reduce bone strength over the course of therapy.

Is Anastrozole Effective?

• Anastrozole is quite effective in improving long-term survival.

• One study showed that the drug provided clinical benefits in 59% of patients, compared with 46% on Tamoxifen.

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

Who Should Not Use Anastrozole?

Anastrozole is not a universal medicine that can be given to any breast cancer patient. Certain patients are not supposed to use Anastrozole, as their risk-benefit ratio is more weighted toward risk. Here are some of them:

• Those who are allergic to Anastrozole.

• Those who are in their premenopausal stage, that is, those having monthly menstruation.

• Those who are pregnant.

What Are the Side Effects of 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, such as liver inflammation. Symptoms that may indicate liver trouble in patients include yellowing of the skin and the whites of the eyes, feeling unwell, and right-sided abdominal pain.

These are the side effects that are seen when Anastrozole is employed in post-menopausal females for the treatment of breast cancer. In addition to breast cancer treatment, Anastrazole can also be advised for gynecomastia in men. The Anastrozole side effects in men appear to be similar to those in postmenopausal women; however, its impact on bone density is relatively lower in males than in postmenopausal women.

Can You Stop Taking Anastrozole Without Your Doctor's Approval?

• The doctor’s approval must be there before stopping the drug, and never stop taking Anastrozole by yourself.

• Remember that you must continue taking Anastrozole regardless of how well you respond to it. You can stop only when your healthcare specialist asks you to.

Are There Any Dietary Restrictions to Consider When Taking Anastrozole?

Anastrozole therapy does not necessarily recommend any relevant dietary modifications. So most patients tend to continue with their normal dietary pattern while on Anastrozole for breast cancer.

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 packaging in which they are being supplied to you.

• 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, and for that, you can make use of the medicine take-back program.

• You can get help from local pharmacists to know about this drug disposal program.

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. Breathing difficulty and seizures are indications that immediate attention is needed, and any delay can bring complications.

For Doctors

Indications

Anastrozole is indicated for the following purposes:

• As an adjuvant treatment in post-menopausal women who have HER2-positive breast cancers.

• 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 where Tamoxifen therapy failed to stop the disease progression.

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:

1. Mechanism of Action

Breast cancer cells often require the stimulatory and maintenance effect of estrogens to grow. The aromatase enzyme in postmenopausal women can convert adrenal androgens (primarily androstenedione and testosterone) into 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.

2. 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 increase TSH levels.

3. Pharmacokinetics

Mean Cmax (Maximum Drug Concentration Achieved): Decreased by 16%.

Median Tmax (Time Taken to Attain the Maximum Concentration): Delayed from 2 to 5 hours upon administration of Anastrozole 30 minutes after food.

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

1. 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%.

2. 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.

3. Excretion

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

4. Elimination

• 85% is carried out by hepatic metabolism.

• 10% is accounted for by renal elimination.

• Mean Elimination Halflife- 50 hours.

Special Considerations

• Renal Impairment - Renal impairment doesn't mandate a change in Anastrozole dosage.

• Hepatic Impairment - Those with mild to moderate hepatic impairment can also take the same standard dose as recommended. 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 - Avoid therapies containing estrogen to ensure 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 benefit compared with 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 with Anastrozole was significantly better than with 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 objective response rates and median times to progression and death were not different between the two groups. Additionally, Anastrozole 10 mg did not demonstrate superiority compared to Anastrozole 1 mg.

Patient Counseling Information

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 with 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 with Anastrozole use.

• 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.