Fulvestrant

Fulvestrant is an Antineoplastic Agent belonging to pharmacology class of Estrogen Derivative

Fulvestrant can be used in the treatment of Breast cancer It is also used to treat Breast cancer in male patients, advanced or metastatic, HR-positive, HER2-negative

Fulvestrant is Slowly absorbed. It is extensively and rapidly distributed, primarily into the extravascular space. Volume of distribution: Approx 3-5 L/kg. Plasma protein binding: 99%, mainly to LDL, VLDL, and HDL fractions and get metabolized mainly in the liver via multiple pathways to form several metabolites which gets excreted mainly via faeces (approx 90%); urine (<1%). Elimination half-life: Approx 40-50 days.

The common side effects of Fulvestrant includes: Hypersensitivity reactions (e.g. angioedema, urticaria), injection site-related events (e.g. neuropathic pain, peripheral neuropathy, sciatica, neuralgia), thromboembolic events, risk of osteoporosis..

Fulvestrant is available in the form of injectable solution.

The molecule is available in India, Japan, Germany, China.

Fulvestrant is an estrogen receptor antagonist; competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that causes a dose-related down-regulation of estrogen receptors and inhibits tumor growth.

Tmax of Fulvestrant was approx 7 days.

Fulvestrant is available in injectable solution.

For IM administration only. Administer 500 mg dose as two 5 mL IM injections (one in each buttocks [gluteal area]) slowly over 1 to 2 minutes per injection. If administering at the dorsogluteal site, use caution during injection due to the proximity of underlying sciatic nerve. Refer to facility policy for IM administration of large volumes.

To prepare each syringe for administration, hold syringe upright; carefully tilt syringe cap back and forth (without twisting) until the cap disconnects for removal; pull cap off by pulling up without touching the syringe tip (to maintain sterility); attach safety needle to syringe tip and twist firmly to lock. Remove needle cap by pulling straight off to avoid damaging needle point, remove needle sheath and expel excess air from syringe prior to administration. Refer to product labeling for detailed instructions.

Fulvestrant can be used in the treatment of Breast cancer It is also used to treat Breast cancer in male patients, advanced or metastatic, HR-positive, HER2-negative.

Fulvestrant is a Antineoplastic Agent similar to endogenous estrogen. In post-menopausal women, Fulvestrant substitutes for the loss of estrogen production and alleviates menopausal symptoms. It also reduces bone resorption and prevents postmenopausal bone loss.

Fulvestrant is approved for use in the following clinical indications

Breast cancer (monotherapy):

Treatment of hormone-receptor (HR)-positive advanced breast cancer in postmenopausal patients with disease progression following endocrine therapy.

Treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal patients not previously treated with endocrine therapy.

Breast cancer (combination therapy):

Treatment of HR-positive, HER2-negative advanced or metastatic breast cancer (in combination with ribociclib) in postmenopausal patients as initial endocrine-based therapy or following disease progression on endocrine therapy.

Treatment of HR-positive, HER2-negative advanced or metastatic breast cancer (in combination with palbociclib or abemaciclib) in females with disease progression following endocrine therapy.

Although not approved there have been certain off labelled uses documented for Fulvestrant which includes:

Breast cancer in male patients, advanced or metastatic, HR-positive, HER2-negative

• Breast cancer, advanced, monotherapy (postmenopausal patients; HR-positive):

IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once monthly

• Breast cancer, advanced, monotherapy (postmenopausal patients; HR-positive, HER2-negative):

IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once monthly

• Breast cancer, advanced or metastatic, combination therapy (postmenopausal patients; 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 ribociclib; continue until disease progression or unacceptable toxicity .

• Breast cancer, advanced or metastatic, combination therapy (second-line endocrine-based combination therapy; pre- or postmenopausal patients, 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; continue until disease progression or unacceptable toxicity.

• Breast cancer, advanced or metastatic, HR-positive, HER2-negative, PIK3CA-mutated (off-label combination): Males and postmenopausal patients:

IM: Initial: 500 mg on days 1, 15, and 29; Maintenance: 500 mg once every 28 days (in combination with alpelisib); continue until disease progression or unacceptable toxicity.

• Breast cancer in male patients, advanced or metastatic, HR-positive, HER2-negative (off-label use):

According to ASCO guidelines for management of male breast cancer, fulvestrant may be used in males with advanced or metastatic HR-positive, HER2-negative breast cancer; males who develop recurrent metastatic, HR-positive, HER2-negative breast cancer while receiving adjuvant endocrine therapy should be offered an alternative endocrine therapy; fulvestrant should not be used in visceral crisis or rapidly progressing disease. Endocrine therapy for males with advanced or metastatic, HR-positive, HER2-negative breast cancer may be sequenced as in females. Metastatic breast cancer in males is treated with the same endocrine therapy as in females

Injectable solution

• Dose Adjustment in Hepatic Patient:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Reduce initial and maintenance doses: Initial: 250 mg on days 1, 15, and 29; Maintenance: 250 mg once monthly.

Severe impairment (Child-Pugh class C)

• Dose Adjustment in Pediatric Patient:

McCune-Albright syndrome (MAS); progressive precocious puberty :

Female children 1 to 10 years: IM: 4 mg/kg once monthly; dosing based on a trial in 30 girls ≤10 years of age (range: 1 to 8.5 years) who received monthly injections for 1 year; significant decrease in vaginal bleeding and reduction in rates of skeletal maturation were reported.

Fulvestrant may be contraindicated in the following conditions:-

Severe hepatic impairment. Pregnancy and lactation.

• Concerns related to adverse effects:

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

• Injection-site reactions:

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.

There is no sufficient scientific evidence traceable regarding use and safety of Fulvestrant in concurrent use with alcohol.

It is not known if fulvestrant is present in breast milk.

Because of the potential for serious adverse reactions in the breastfed infant, lactating patients should not breastfeed during treatment and for 1 year after the final fulvestrant dose.

The adverse reactions related to Fulvestrant can be categorized as

Common Adverse effects:

Hypersensitivity reactions (e.g. angioedema, urticaria), injection site-related events (e.g. neuropathic pain, peripheral neuropathy, sciatica, neuralgia), thromboembolic events, risk of osteoporosis.

Less Common Adverse effects:

Nausea, vomiting, diarrhea.

Rare Adverse effects:

Neuralgia, peripheral neuropathy, sciatica.

The most common side effects of Fulvestrant includes: Hypersensitivity reactions (e.g. angioedema, urticaria), injection site-related events (e.g. neuropathic pain, peripheral neuropathy, sciatica, neuralgia), thromboembolic events, risk of osteoporosis.

• Geriatric

In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).

• Gender

Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.

• Race

In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.

Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

• Pharmacodynamics:

In a clinical study in postmenopausal women with primary breast cancer treated with single doses of Fulvestrant 15-22 days prior to surgery, there was evidence of increasing downregulation of ER with increasing dose. This was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation. .

• Pharmacokinetics:

Absorption:

Slowly absorbed. Time to peak plasma concentration: Approx 7 days.

Distribution:

Extensively and rapidly distributed, primarily into the extravascular space. Volume of distribution: Approx 3-5 L/kg. Plasma protein binding: 99%, mainly to LDL, VLDL, and HDL fractions.

Metabolism:

Metabolized mainly in the liver via multiple pathways to form several metabolites.

Excretion:

Mainly via faeces (approx 90%); urine (<1%). Elimination half-life: Approx 40-50 days.

1. https://www.uptodate.com/contents/ Fulvestrant -drug-information?search= Fulvestrant &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Fulvestrant _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Fulvestrant ?type=full&mtype=generic#mechanism-of-action