Fulvestrant

L02B - Hormone antagonists and related agents ATC L02BA03 Small molecule approved 2002 Parenteral

JFDA label: Faslodex 250mg/5ml PFS

Mechanism of Action

Antagonist of Estrogen receptor — Estrogen receptor alpha antagonist; Degrader of Estrogen receptor — Estrogen receptor degrader

Target	Action	Gene / class
Estrogen receptor efficacy	ANTAGONIST	ESR1

Indications

Approved

Breast cancer, advanced
Breast cancer, advanced or metastatic (second-line endocrine-based combination therapy)

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Pregnant or lactating women Absolute
Known hypersensitivity to fulvestrant or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Very Common Fatigue · headache

Hepatobiliary disorders (3)

Very Common Increased liver enzymes

Common Increased serum ALT · increased serum AST

Blood and lymphatic system disorders (5)

Very Common Anemia

Common Decreased platelet count · febrile neutropenia · leukopenia · neutropenia

Metabolism and nutrition disorders (1)

Very Common Hot flash

Gastrointestinal disorders (8)

Very Common constipation · Nausea · stomatitis

Common anorexia · Decreased appetite · diarrhea · dysgeusia · vomiting

Skin and subcutaneous tissue disorders (3)

Common Alopecia · skin rash · xeroderma

Musculoskeletal and connective tissue disorders (7)

Very Common Arthralgia

Common back pain · limb pain · musculoskeletal pain · myalgia · Ostealgia · weakness

Eye disorders (3)

Common Blurred vision · dry eye syndrome · increased lacrimation

Infections and infestations (1)

Very Common Infection

General disorders and administration site conditions (1)

Very Common Pain at injection site

Respiratory, thoracic and mediastinal disorders (3)

Common Cough · dyspnea · epistaxis

Dosing

Source: Lexicomp

Breast cancer, advanced (postmenopausal women; HR positive): IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once monthly. In a monotherapy dose comparison study, the once monthly maintenance dose was administered at 28 days ± 3 days (Di Leo 2014). Breast cancer, advanced (postmenopausal women; HR positive, HER2-negative): IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once monthly. In a monotherapy dose comparison study, the once monthly maintenance dose was administered at 28 days ± 3 days (Di Leo 2014). Breast cancer, advanced or metastatic (second-line endocrine-based combination therapy): Adult females (HR positive, HER2 negative): IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once every 28 days. Administer in combination with palbociclib or abemaciclib (and an LHRH/GnRH agonist [eg, goserelin] if pre- or perimenopausal); continue until disease progression or unacceptable toxicity (Sledge 2017; Turner 2015). Note: Refer to Palbociclib or Abemaciclib monograph for dosing in combination with fulvestrant.

Refer to adult dosing.

Warnings & Precautions

Source: Lexicomp

Hypersensitivity

Hypersensitivity reactions, including urticaria and angioedema, have been reported.

Injection-site related events

Events related to injection site, including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported with fulvestrant administration. Due to the proximity of underlying sciatic nerve, use caution if administering at the dorsogluteal site. Disease-related concerns:

Bleeding disorders

Use with caution in patients with a history of bleeding disorders (including thrombocytopenia) and/or patients on anticoagulant therapy; bleeding/hematoma may occur from IM administration.

Hepatic impairment

Exposure is increased and dosage adjustment is recommended in patients with moderate impairment. Safety and efficacy have not been established in severe impairment. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, fulvestrant may cause fetal harm if administered during pregnancy. For females of reproductive potential, pregnancy testing is recommended within 7 days prior to initiation of fulvestrant and effective contraception should be used during treatment and for 1 year after the last fulvestrant dose. Animal data suggest that fulvestrant may affect female and male fertility (although not approved for use in men).

Lactation

It is not known if fulvestrant is present in breast milk. Because of the potential for serious adverse reactions in the breastfed infant, lactating women should not breastfeed during treatment and for 1 year after the final fulvestrant dose.

Monitoring

Clinical pearl	Liver function tests; pregnancy testing is recommended within 7 days prior to fulvestrant initiation (for females of reproductive potential); monitor for signs/symptoms of bleeding

Chemistry & Properties

Formula	C32H47F5O3S
Molecular weight	606.78 g/mol
IUPAC name	(7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
CAS	129453-61-8
PubChem CID	104741
InChIKey	`VWUXBMIQPBEWFH-WCCTWKNTSA-N`
logP	8.68 (XLogP 9.2)
Polar surface area	63.52 Å²
H-bond acceptors / donors	3 / 2
Drug-likeness (QED)	0.13
Lipinski violations	2

SMILES

C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC[S+]([O-])CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.791 h
Volume of distribution	1.027 L/kg
Protein binding	98.8%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—

Receptor binding (top 3)

Target	Action	Affinity
Estrogen receptor-α (ESR1)	Antagonist	pKi 9.0
Estrogen receptor-β (ESR2)	Antagonist	pKi 8.9
GPER (GPER1)	Agonist	pKi 7.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (1, DDInter)

Interacting drug	Severity	Management
Omacetaxine mepesuccinate	moderate

Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Fulvestrant EVER Pharma	Pre-filled Syringe 250 mg/5 ml	2 PFS	Sabbagh Drug Store	125.740
Estroquin	Pre-filled Syringe 250 mg/5 ml	2 PFS	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Faslodex 250mg/5ml PFS	Pre-filled Syringe 50 mg/ml	2 PFS	Shawi & Rushedat Drug Store	—