Anastrozole

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Drugbox Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer.<ref name=Label2018>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=AHFS2016/> Specifically it is used for hormone receptor-positive breast cancer.<ref name=AHFS2016/> It has also been used to prevent breast cancer in those at high risk.<ref name=AHFS2016/> It is taken orally.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects of anastrozole include hot flashes, altered mood, joint pain, and nausea.<ref name=AHFS2016/><ref name=Label2018/> Severe side effects include an increased risk of heart disease and osteoporosis.<ref name=AHFS2016/> Use during pregnancy may harm the baby.<ref name=AHFS2016/> Anastrozole is in the aromatase-inhibiting family of medications.<ref name=AHFS2016/> It works by blocking the production of estrogens in the body, and hence has antiestrogenic effects.<ref name=AHFS2016/>

Anastrozole was patented in 1987 and was approved for medical use in 1995.<ref name=Fis2006>Template:Cite book</ref><ref name=Dukes1997>Template:Cite journal</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> Anastrozole is available as a generic medication.<ref name=AHFS2016/> In 2022, it was the 179th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Breast cancer

Anastrozole is used in the treatment and prevention of breast cancer in women.<ref name="AHFS2016" /> The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was of localized breast cancer and women received either anastrozole, the selective estrogen receptor modulator tamoxifen, or both for five years, followed by five years of follow-up.<ref name="ATAC">Template:Cite journal Template:Primary-inline</ref> After more than 5 years the group that received anastrozole had better results than the tamoxifen group.<ref name="ATAC"/> The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized estrogen receptor-positive breast cancer.<ref name="ATAC"/>

Early puberty

Anastrozole is used at a dosage of 0.5 to 1 mg/day in combination with the antiandrogen bicalutamide in the treatment of peripheral precocious puberty, for instance due to familial male-limited precocious puberty (testotoxicosis) and McCune–Albright syndrome, in boys.<ref name="FDALabel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="SchoelwerEugster2015">Template:Cite book</ref><ref name="pmid31144045">Template:Cite book</ref><ref name="KliegmanStanton2015">Template:Cite book</ref><ref name="pmid29292624">Template:Cite journal</ref><ref name="HaddadEugster2012">Template:Cite book</ref><ref name="HaddadEugster2019">Template:Cite journal</ref><ref name="MisraRadovick2018">Template:Cite book</ref><ref name="Mauras2011">Template:Cite journal</ref><ref name="Fuqua2013">Template:Cite journal</ref>

Available forms

Anastrozole is available in the form of 1 mg oral tablets.<ref name=Label2018 /><ref name="WhiteBradnam2015">Template:Cite book</ref> No alternative forms or routes are available.<ref name="WhiteBradnam2015" />

Contraindications

Contraindications of anastrozole include hypersensitivity to anastrozole or any other component of anastrozole formulations, pregnancy, and breastfeeding.<ref name=Label2018 /> Hypersensitivity reactions to anastrozole including anaphylaxis, angioedema, and urticaria have been observed.<ref name=Label2018 />

Side effects

Common side effects of anastrozole (≥10% incidence) include hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, bone fractures, back pain, insomnia, headache, bone pain, peripheral edema, coughing, dyspnea, pharyngitis, and lymphedema.<ref name=Label2018 /> Serious but rare adverse effects (<0.1% incidence) include skin reactions such as lesions, ulcers, or blisters; allergic reactions with swelling of the face, lips, tongue, and/or throat that may cause difficulty swallowing or breathing; and abnormal liver function tests as well as hepatitis.<ref name=Label2018 />

Interactions

Anastrozole is thought to have clinically negligible inhibitory effects on the cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2D6, CYP2C8, CYP2C9, and CYP2C19.<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /><ref name=Label2018 /> As a result, it is thought that drug interactions of anastrozole with cytochrome P450 substrates are unlikely.<ref name="SanfordPlosker2008" /> No clinically significant drug interactions have been reported with anastrozole as of 2003.<ref name="Lonning2003" />

Anastrozole does not affect circulating levels of tamoxifen or its major metabolite N-desmethyltamoxifen.<ref name="Lonning2003" /><ref name="Lønning2003" /> However, tamoxifen has been found to decrease steady-state area-under-the-curve levels of anastrozole by 27%.<ref name="Lonning2003" /><ref name="Lønning2003" /> But estradiol levels were not significantly different in the group that received both anastrozole and tamoxifen compared to the anastrozole alone group, so the decrease in anastrozole levels is not thought to be clinically important.<ref name="SanfordPlosker2008" />

Pharmacology

Pharmacodynamics

Anastrozole works by reversibly binding to the aromatase enzyme, and through competitive inhibition blocks the conversion of androgens to estrogens in peripheral (extragonadal) tissues.<ref name="pmid14623515">Template:Cite journal</ref> The medication has been found to achieve 96.7% to 97.3% inhibition of aromatase at a dosage of 1 mg/day and 98.1% inhibition of aromatase at a dosage of 10 mg/day in humans.<ref name="Lonning2003">Template:Cite journal</ref><ref name="Lønning2003">Template:Cite journal</ref> As such, 1 mg/day is considered to be the minimal dosage required to achieve maximal suppression of aromatase with anastrozole.<ref name="Lonning2003" /> This decrease in aromatase activity results in an at least 85% decrease in estradiol levels in postmenopausal women.<ref name="Lonning2003" /> Levels of corticosteroids and other adrenal steroids are unaffected by anastrozole.<ref name="Lonning2003" />

Pharmacokinetics

The bioavailability of anastrozole in humans is unknown, but it was found to be well-absorbed in animals.<ref name="Lønning2003" /><ref name=Label2018 /> Absorption of anastrozole is linear over a dosage range of 1 to 20 mg/day in humans and does not change with repeated administration.<ref name="Lonning2003" /><ref name="SanfordPlosker2008" /><ref name=Label2018 /> Food does not significantly influence the extent of absorption of anastrozole.<ref name="SanfordPlosker2008" /><ref name=Label2018 /> Peak levels of anastrozole occur a median 3 hours after administration, but with a wide range of 2 to 12 hours.<ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> Steady-state levels of anastrozole are achieved within 7 to 10 days of continuous administration, with 3.5-fold accumulation.<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> However, maximal suppression of estradiol levels occurs within 3 or 4 days of therapy.<ref name="Lonning2003" />

Active efflux of anastrozole by P-glycoprotein at the blood–brain barrier has been found to limit the central nervous system penetration of anastrozole in rodents, whereas this was not the case with letrozole and vorozole.<ref name="CostaCarneiro2016">Template:Cite journal</ref><ref name="RussellCheung2017">Template:Cite journal</ref><ref name="MiyajimaKusuhara2013">Template:Cite journal</ref> As such, anastrozole may have peripheral selectivity in humans, although this has yet to be confirmed.<ref name="MiyajimaKusuhara2013" /> In any case, estradiol is synthesized peripherally and readily crosses the blood–brain barrier, so anastrozole would still expected to reduce estradiol levels in the central nervous system to a certain degree. The plasma protein binding of anastrozole is 40%.<ref name="Lonning2003" /><ref name="SanfordPlosker2008" />

The metabolism of anastrozole is by N-dealkylation, hydroxylation, and glucuronidation.<ref name="Lonning2003" /> Inhibition of aromatase is due to anastrozole itself rather than to metabolites, with the major circulating metabolite being inactive.<ref name=Label2018 /> The elimination half-life of anastrozole is 40 to 50 hours (1.7 to 2.1 days).<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> This allows for convenient once-daily administration.<ref name="SanfordPlosker2008" /> The medication is eliminated predominantly by metabolism in the liver (83 to 85%) but also by residual excretion by the kidneys unchanged (11%).<ref name="Lonning2003" /><ref name="Lønning2003" /><ref name="SanfordPlosker2008" /> Anastrozole is excreted primarily in urine but also to a lesser extent in feces.<ref name="SanfordPlosker2008" />

Chemistry

Anastrozole is a nonsteroidal benzyl triazole.<ref name="Lonning2003" /><ref name="SanfordPlosker2008">Template:Cite journal</ref> It is also known as α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-m-benzenediacetonitrile.<ref name="Drugs.com" /> Anastrozole is structurally related to letrozole, fadrozole, and vorozole, with all being classified as azoles.<ref name="Thurston2006">Template:Cite book</ref><ref name="Kunal2015">Template:Cite book</ref><ref name="SmithAllerton2012">Template:Cite book</ref><ref>Template:Cite book</ref>

History

Anastrozole was patented by Imperial Chemical Industries (ICI) in 1987 and was approved for medical use, specifically the treatment of breast cancer, in 1995.<ref name="Fis2006" /><ref name="Dukes1997" />

Society and culture

Generic names

Anastrozole is the generic name of the drug and its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink.<ref name="Drugs.com" />

Brand names

Anastrozole is primarily sold under the brand name Arimidex.<ref name="Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, it is also marketed under a variety of other brand names throughout the world.<ref name="Drugs.com" />

Availability

Anastrozole is available widely throughout the world.<ref name="Drugs.com" />

Research

Anastrozole is surprisingly ineffective at treating gynecomastia, in contrast to selective estrogen receptor modulators like tamoxifen.<ref name="SungFagerlund2015">Template:Cite journal</ref><ref name="BedognettiRubagotti2010">Template:Cite journal</ref>

Anastrozole was under development for the treatment of female infertility but did not complete development and hence was never approved for this indication.<ref name="AdisInsight-1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

An anastrozole and levonorgestrel vaginal ring (developmental code name BAY 98–7196) was under development for use as a hormonal contraceptive and treatment for endometriosis, but development was discontinued in November 2018 and the formulation was never marketed.<ref name="AdisInsight-2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Anastrozole increases testosterone levels in males and has been studied as an alternative method of androgen replacement therapy in men with hypogonadism.<ref name="SerefogluGokce2013">Template:Cite book</ref><ref name="KheraAdaikan2016">Template:Cite journal</ref> However, there are concerns about its long-term influence on bone mineral density in this patient population, as well as other adverse effects.<ref name="SerefogluGokce2013" />