FULVESTRANT VIATRIS

Indications

• Hormone receptor-positive breast cancer in postmenopausal women
• Treatment of breast cancer that is resistant to tamoxifen
• Chemoprevention in women at moderate-to-high risk of breast cancer
• Prevention of gynaecomastia in men undergoing long-term bicalutamide treatment

Dosage

Adults: Initially 500 mg deep intramuscularly every 2 weeks for the first 3 doses, then 500 mg monthly.

Mechanism of action

Fulvestrant competitively and reversibly binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two mechanisms: it downregulates the receptors so that estrogen cannot bind, and it degrades the receptors to which it is bound. This dual action inhibits the growth of both tamoxifen-resistant and estrogen-sensitive breast cancer cell lines.

Pharmacodynamics

Fulvestrant acts as an estrogen receptor antagonist without known agonist effects. It is specifically designed to have no peripheral steroidal effects in postmenopausal women, as indicated by stable plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) after administration.

Pharmacokinetics

Fulvestrant is administered via deep intramuscular injection, with a typical dosage of 500 mg for the first three doses, followed by 500 mg monthly. The drug has a long half-life, allowing for once-monthly dosing after the initial loading doses. It is primarily metabolized in the liver, and caution is advised in patients with hepatic impairment due to potential increased exposure.

Contra-indications

• Severe hepatic impairment
• Personal or family history of idiopathic venous thromboembolism
• Genetic predisposition to thromboembolism

Adverse effects

• Alopecia
• Anaemia
• Cataract
• Cerebral ischaemia
• Constipation
• Diarrhoea
• Dizziness
• Hypertriglyceridaemia
• Muscle complaints
• Nausea
• Vision impairment
• Leucopenia
• Pancreatitis
• Thrombocytopenia

Precautions

• Caution in mild to moderate hepatic impairment
• Avoid in severe hepatic impairment

Pregnancy

Manufacturer advises to avoid due to potential risk of fetal abnormalities and death in animal studies.

Breast-feeding

Manufacturer advises to avoid.

Storage

Store in a refrigerator (2 to 8 degrees Celsius). Do not freeze. Protect from light.

Formulations

• Faslodex 250mg/5ml solution for injection (pre-filled syringe)

Mechanism of action

Fulvestrant competitively and reversibly binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, fulvestrant binds to the receptors and downregulates them so that estrogen is no longer able to bind to these receptors. Second, fulvestrant degrades the estrogen receptors to which it is bound. Both of these mechanisms inhibit the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines. Fulvestrant, a 7(alpha)-alkylsulfinyl analog of estradiol, is an estrogen antagonist. Data from animal studies indicate that fulvestrant does not possess estrogen-agonist activity. The drug competitively binds to and downregulates estrogen receptors in human breast cancer cells. Fulvestrant has been shown to inhibit the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer (MCF-7) cell lines in vitro and in vivo. Data from studies in animals indicate that the drug also may block the uterotropic action of estradiol. Fulvestrant does not appear to exhibit peripheral steroidal effects in postmenopausal women, as evidenced by an absence of appreciable changes in plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) after receiving 250 mg of fulvestrant IM monthly. The efferent ductules express the highest amount of estrogen receptors ESR1 (ERalpha) and ESR2 (ERbeta) within the male reproductive tract. Treatment of rats with the antiestrogen fulvestrant (ICI 182,780) causes inhibition of fluid reabsorption in the efferent ductules, leading to seminiferous tubule atrophy and infertility. To provide a more comprehensive knowledge about the molecular targets for estrogen in the rat efferent ductules, /the authors/ investigated the effects of ICI 182,780 treatment on gene expression using a microarray approach. Treatment with ICI 182,780 increased or reduced at least 2-fold the expression of 263 and 98 genes, respectively. Not surprisingly, several genes that encode ion channels and macromolecule transporters were affected. Interestingly, treatment with ICI 182,780 markedly altered the expression of genes related to extracellular matrix organization. Matrix metalloproteinase 7 (Mmp7), osteopontin (Spp1), and neuronal pentraxin 1 (Nptx1) were among the most altered genes in this category. Upregulation of Mmp7 and Spp1 and downregulation of Nptx1 were validated by Northern blot. Increase in Mmp7 expression was further confirmed by immunohistochemistry and probably accounted for the decrease in collagen content observed in the efferent ductules of ICI 182,780-treated animals. Downregulation of Nptx1 probably contributed to the extracellular matrix changes and decreased amyloid deposition in the efferent ductules of ICI 182,780-treated animals. Identification of new molecular targets for estrogen action may help elucidate the regulatory role of this hormone in the male reproductive tract. Fulvestrant is a pure antiestrogen that emerged from a systematic medicinal chemistry strategy of modification of long-chain alkyl substitutes in the 7a-position of estradiol. Fulvestrant has no uterotrophic effects on the immature or ovariectomized rat and blocks the agonistic effects of estradiol and tamoxifen in a dose-dependent manner. In in vivo and in vitro breast cancer models, fulvestrant has anticancer activity at least as good as tamoxifen and is superior to tamoxifen in some models. Fulvestrant requires intramuscular administration in a proprietary formulation of castor oil and alcohols. When fulvestrant binds to estrogen receptor monomers it inhibits receptor dimerization, activating function 1 (AF1) and AF2 are rendered inactive, translocation of receptor to the nucleus is reduced, and degradation of the estrogen receptor is accelerated. This results in pure antiestrogenic effects. ... Estrogen and tamoxifen activate large conductance Ca(2+)-activated K(+) (BK(Ca)) channels in smooth muscle throu

Pharmacodynamics

Fulvestrant for intramuscular administration is an estrogen receptor antagonist without known agonist effects.