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Faslodex

Pronunciation

Generic Name: Fulvestrant
Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 4′ - [2 - [[(2aE,4E,5′S,6S,6′R,7R,8E,11R,13R,15S,17aR,20R,20aR,20bS) - 6′ - Ethyl - 3′,4′,5′,6,6′,7,10,11,14,15,17a,20,20a,20b - tetradecahydro - 20,20b - dihydroxy - 5′,6,8,19 - furo[4,3,2 - pq][2,6]benzodioxacyclooctadecin - 13,2′[2H]pyran] - 7 - yl]oxy]ethyl] - N - methylmethanesulfonanilide
Molecular Formula: C32H47F5O3S
CAS Number: 129453-61-8

Introduction

Antineoplastic agent; estrogen antagonist.1 2

Uses for Faslodex

Breast Cancer

Treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen (e.g., tamoxifen) therapy.1 2 4 7

Slideshow: Flashback: FDA Drug Approvals 2013

Efficacy in premenopausal women (e.g., those with functioning ovaries, as evidenced by menstruation and/or premenopausal LH, FSH, and estradiol concentrations) with advanced breast cancer not established.1

Faslodex Dosage and Administration

General

  • Commercially available as two 5-mL prefilled syringes, each containing 250 mg of fulvestrant, with safety needles.1 4

  • Consult manufacturer’s prescribing information for details on assembly and proper use of safety needle.1

Administration

IM Administration

Administer IM slowly (over 1–2 minutes per injection) at the dorsogluteal site or into the upper outer quadrant of the gluteal muscle.1 3

Administer 500-mg dose as 2 concurrent 250-mg (5-mL) injections, which may be administered bilaterally.1

Prior to administration, remove injection from refrigeration and keep at room temperature for up to 1 hour or roll gently between the hands.3 4

Dosage

Adults

Breast Cancer
IM

500 mg on days 1, 15, and 29 and then once monthly thereafter.1 2 7 This regimen associated with longer progression-free survival and similar adverse effects compared with previously recommended regimen (250 mg once monthly without a loading dose regimen).1 7

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.1

Moderate hepatic impairment (Child-Pugh class B): 250 mg (as single injection) on days 1, 15, and 29 and then once monthly thereafter.1 (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (Child-Pugh class C): Safety and efficacy not established.1

Geriatric Patients

Dosage adjustments not required.1

Cautions for Faslodex

Contraindications

  • Known hypersensitivity to fulvestrant or any ingredient in the formulation (e.g., benzyl alcohol).1 4

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including urticaria and angioedema, reported.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 teratogenicity and embryolethality demonstrated in animals.1

Avoid pregnancy during therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Hematologic Disorders

Use with caution in patients with bleeding diatheses or thrombocytopenia and in those receiving anticoagulant therapy because of IM administration.1

Specific Populations

Pregnancy

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

Lactation

Distributed into milk in rats; not known whether fulvestrant is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Used in a limited number of girls 1–8 years of age with progressive precocious puberty associated with McCune-Albright syndrome; however, efficacy not established.1 Common adverse effects included injection site reactions (e.g., inflammation, pain, hematoma, pruritus, rash), abdominal pain, contusion, tachycardia, vasodilation (hot flush), extremity pain, and vomiting.1 Effects on bone mineral density not elucidated.1

Geriatric Use

Slightly lower objective response rates in patients ≥65 years of age than in younger adults.1 No substantial difference in pharmacokinetics relative to younger adults.1

Hepatic Impairment

Systemic exposure increased in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics). Safety and efficacy not established in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Not studied in patients with renal impairment; however plasma fulvestrant concentrations in women with Clcr ≥30 mL/minute were similar to those in women with normal renal function.1

Common Adverse Effects

Adverse GI effects1 2 7 (e.g., nausea,1 5 6 vomiting,1 5 6 constipation,1 5 6 diarrhea,1 5 6 abdominal pain1 5 6 ), headache,1 5 6 pain1 5 6 (e.g., back pain,1 5 bone pain,1 5 6 musculoskeletal pain,1 extremity pain,1 pelvic pain1 5 ), asthenia,1 5 6 vasodilation (hot flushes),1 2 5 6 7 pharyngitis,1 5 6 dyspnea,1 5 injection site reactions7 (e.g., pain1 5 ), increased cough,1 5 anorexia,1 5 6 peripheral edema,1 5 rash,1 5 chest pain,1 flu syndrome,1 dizziness,1 5 insomnia,1 5 fever,1 5 paresthesia,1 5 urinary tract infection,1 depression,1 anxiety,1 sweating,1 fatigue,1 arthralgia,1 joint disorder.5 6 7

Interactions for Faslodex

Metabolized by CYP3A4 and non-CYP routes.1

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, or 3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Pharmacokinetic interactions unlikely.1 No dosage adjustment needed.1

Inducers of CYP3A4: Pharmacokinetic interactions unlikely.1 No dosage adjustment needed.1

Specific Drugs

Drug

Interaction

Comments

Ketoconazole

Pharmacokinetic interactions unlikely1

Midazolam

Pharmacokinetic interactions unlikely1

Rifampin

Pharmacokinetic interactions unlikely1

Faslodex Pharmacokinetics

Absorption

Bioavailability

Following IM administration of 500 mg every 2 weeks for the first month of therapy, steady-state plasma concentrations are attained within the first month.1 Following IM injection of 250 mg once every month (without loading dose regimen), steady-state plasma concentrations are attained after 3–6 doses.8 9 10

Distribution

Extent

Distributed principally into the extravascular space.1

Has been shown to cross the placenta and distribute into milk in rats.1

Plasma Protein Binding

99% (mainly VLDL, LDL, and HDL lipoprotein fractions).1

Elimination

Metabolism

Metabolized mainly in the liver.1 Fulvestrant metabolism appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids.1 Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models.1

In vitro studies indicate that CYP3A4 is the only enzyme involved in fulvestrant oxidation; however, the relative contribution of CYP and non-CYP routes in vivo currently is not known.1

Elimination Route

Rapidly cleared by the hepatobiliary route with excretion primarily via feces (approximately 90%); renal elimination is negligible (<1%).1

Half-life

Approximately 40 days.1

Special Populations

Mild hepatic impairment (Child-Pugh class A) does not substantially alter systemic exposure or clearance.1 Moderate hepatic impairment (Child-Pugh class B) increases systemic exposure by 70%.1

Stability

Storage

Parenteral

Injection

Refrigerate at 2–8°C.1 Protect from light; store in original carton until time of use.1

Actions

  • An estrogen antagonist; a 7α-alkylsulfinyl analog of estradiol.1 2

  • Does not possess estrogen-agonist activity.1

  • Competitively binds to and down-regulates estrogen receptors in human breast cancer cells.1 2 Reductions in estrogen-receptor levels, as well as associated reductions in progesterone-receptor levels and associated antiproliferative effects, appear to be dose related.1 12

  • Inhibits the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer (MCF-7) cell lines in vitro and in vivo.1 2

  • May block the uterotropic action of estradiol.1 2

  • Does not exhibit peripheral steroidal effects in postmenopausal women.1

Advice to Patients

  • Necessity of advising women of childbearing potential to use an effective method of contraception while receiving therapy.4 Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

  • Importance of discontinuing the drug and informing clinician if an allergic or hypersensitivity reaction occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fulvestrant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IM use only

50 mg/mL (250 mg)

Faslodex (two 5-mL prefilled disposable syringes)

AstraZeneca

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 8, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. AstraZeneca. Faslodex (fulvestrant) injection prescribing information. Wilmington, DE; 2011 Dec.

2. Curran M, Wiseman L. Fulvestrant. Drugs. 2001; 61:807-13. [PubMed 11398912]

3. Faslodex (fulvestrant) injection: monthly intramuscular injection. From Faslodex website. Accessed 2012 Feb 2. ()

4. AstraZeneca, Wilmington, DE: personal communication

5. Osborne CK, Pippen J, Jones SE et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20:3386-95

6. Howell A, Robertson JFR, Albano JQ et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396-403

7. Di Leo A, Jerusalem G, Petruzelka L et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010; 28:4594-600. [PubMed 20855825]

8. Howell A, Robertson JF, Abram P et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004; 22:1605-13. [PubMed 15117982]

9. McCormack P, Sapunar F. Pharmacokinetic profile of the fulvestrant loading dose regimen in postmenopausal women with hormone receptor-positive advanced breast cancer. Clin Breast Cancer. 2008; 8:347-51. [PubMed 18757262]

10. Erikstein B, Robertson JFR, Osborne CK et al. ICI 182,780 (’Faslodex’) 250 Mg Monthly Intramuscular (I.M.) Injection Shows Consistent PK Profile When Given as Either 1 x 5 ml or 2 x 2.5 ml Injections in Postmenopausal Women with Advanced Breast Cancer (ABC). Proc Am Soc Clin Oncol. 2001; 20 (American Society of Clinical Oncology Annual Meeting Abstracts):Abstract No. 2025.

11. Chia S, Gradishar W, Mauriac L et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008; 26:1664-70. [PubMed 18316794]

12. Robertson JF, Nicholson RI, Bundred NJ et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res. 2001; 61:6739-46. [PubMed 11559545]

13. Pritchard KI, Rolski J, Papai Z et al. Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2). Breast Cancer Res Treat. 2010; 123:453-61. [PubMed 20632084]

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