Fulvestrant

Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity for the receptor comparable to that of oestradiol. It blocks the growth-promoting actions of oestrogen on hormone-dependent breast cancer cells and has no partial agonist (oestrogen-like) activity of its own. It is given as a long-acting intramuscular injection that is absorbed slowly.

Mechanism of Action

• Receptor antagonism: fulvestrant binds competitively and reversibly to the oestrogen receptor in cancer cells, so oestrogen can no longer bind. It has no known agonist effects.
• Receptor downregulation: binding is followed by a fall in the level of ER protein, and the bound receptor is degraded. In postmenopausal women with primary breast cancer, fulvestrant significantly reduced ER protein in ER-positive tumours compared with placebo.
• Progesterone receptor: expression of the progesterone receptor also fell significantly, consistent with the absence of any intrinsic oestrogen-like effect.
• Dose and tumour markers: in postmenopausal women treated before surgery, 500 mg reduced ER and the proliferation marker Ki67 to a greater degree than 250 mg.
• Tamoxifen-resistant cells: in laboratory studies it inhibited the growth of both tamoxifen-resistant and oestrogen-sensitive human breast cancer cell lines.

Pharmacokinetics

• Absorption: after intramuscular injection, fulvestrant is absorbed slowly and peak plasma concentrations are reached after about 5 days. The 500 mg regimen brings exposure to, or close to, steady state within the first month. At steady state the mean values were AUC 475 ng·days/mL, Cmax 25.1 ng/mL and Cmin 16.3 ng/mL, with up to about a 3-fold difference between peak and trough. Exposure is roughly proportional to dose between 50 and 500 mg.
• Distribution: extensive and rapid. The apparent volume of distribution at steady state is about 3–5 L/kg, which suggests mainly extravascular distribution. About 99% is bound to plasma proteins, chiefly the very low, low and high density lipoprotein fractions.
• Metabolism: not fully characterised. Several pathways analogous to those of endogenous steroids are involved, and the identified metabolites (17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide) are either less active or similar in activity to fulvestrant. In vitro, CYP3A4 is the only P450 enzyme that oxidises fulvestrant, but non-P450 routes appear to predominate in the body. Fulvestrant does not inhibit CYP450 enzymes in vitro.
• Elimination: it is eliminated mainly as metabolites, chiefly in the faeces; less than 1% appears in the urine. Clearance is high (11 ± 1.7 mL/min/kg), consistent with a high hepatic extraction ratio. After intramuscular injection the terminal half-life is governed by the absorption rate and is estimated at 50 days.
• Special populations: exposure may be increased in hepatic impairment, so fulvestrant is used with caution in mild to moderate impairment and is contraindicated in severe impairment. No dose adjustment is recommended in mild to moderate renal impairment.

Fulvestrant (Faslodex) is indicated:

• Monotherapy: oestrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women who have not previously been treated with endocrine therapy, or who have disease relapse on or after adjuvant antioestrogen therapy, or disease progression on antioestrogen therapy.
• In combination with palbociclib: hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women who have received prior endocrine therapy. In pre- or perimenopausal women, the combination with palbociclib should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

• Hypersensitivity to fulvestrant or to any of the excipients.
• Pregnancy and breast-feeding (lactation).
• Severe hepatic impairment.

In the pooled monotherapy data, the most frequently reported side effects were injection site reactions, asthenia, nausea and raised liver enzymes (ALT, AST, ALP). The frequencies below come from the 500 mg groups of the main studies (CONFIRM, FINDER 1 and 2, NEWEST and FALCON); where the pooled data and FALCON differ, the higher frequency is shown. They count all reported events whether or not the investigator linked them to treatment, so for anorexia, venous thromboembolism, raised liver enzymes and bilirubin, back pain and asthenia the share due to fulvestrant cannot be separated from the underlying disease. The median duration of fulvestrant 500 mg treatment in these data was 6.5 months.

Very common (≥1/10): hypersensitivity reactions, hot flushes, nausea, raised liver enzymes (ALT, AST, ALP), rash, joint and musculoskeletal pain, asthenia, injection site reactions.

Common (≥1/100 to <1/10): urinary tract infections, reduced platelet count, anorexia, headache, venous thromboembolism, vomiting, diarrhoea, raised bilirubin, back pain, vaginal haemorrhage, peripheral neuropathy, sciatica.

Uncommon (≥1/1,000 to <1/100): anaphylactic reactions, hepatic failure, hepatitis, raised gamma-GT, vaginal moniliasis (thrush), leucorrhoea, injection site haemorrhage, injection site haematoma, neuralgia.

The term injection site reactions leaves out injection site bleeding and bruising, sciatica, neuralgia and peripheral neuropathy, which are listed separately. Joint and musculoskeletal pain is mostly arthralgia, less often musculoskeletal pain, myalgia or pain in the limbs. Hepatic failure and neuralgia did not occur in the main studies, so their ‘uncommon’ category is a statistical upper limit rather than an observed rate.

Anaphylactic reactions, hepatic failure and hepatitis, venous thromboembolism, and nerve-related events at the injection site (sciatica, neuralgia, neuropathic pain, peripheral neuropathy) are the most important serious reactions. In the FALCON study, joint and musculoskeletal pain was reported by 65 patients on fulvestrant (31.2%); about two-thirds of these reports came within the first 3 months, and none was grade 3 or higher or led to a dose change or to stopping treatment.

Combination with Palbociclib

The safety profile of the combination comes from 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in the PALOMA3 study (345 on fulvestrant plus palbociclib, 172 on fulvestrant plus placebo). The most common reactions of any grade (≥20%) were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, thrombocytopenia and vomiting. The most common grade 3 or higher reactions (≥2%) were neutropenia, leukopenia, infections, anaemia, raised AST, thrombocytopenia and fatigue.

Very common (≥1/10): infections, neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, nausea, stomatitis, diarrhoea, vomiting, alopecia, rash, fatigue, pyrexia, raised AST.

Common (≥1/100 to <1/10): dysgeusia, increased lacrimation, blurred vision, dry eye, epistaxis, dry skin, asthenia, raised ALT.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia.

Neutropenia of any grade occurred in 84.1% of patients on the combination (grade 3 in 58.0%, grade 4 in 11.6%) compared with 3.5% on fulvestrant plus placebo. The median time to the first episode was 15 days and the median duration of grade 3 or higher neutropenia was 16 days. Febrile neutropenia was reported in 3 patients (0.9%).

• CYP3A4 inducers and inhibitors: fulvestrant is oxidised by CYP3A4 in vitro, but clinical interaction studies with rifampicin (an inducer) and ketoconazole (an inhibitor) showed no clinically relevant change in fulvestrant clearance. No dose adjustment is needed with CYP3A4 inhibitors or inducers.
• Effect on other medicines: a clinical study with a sensitive CYP3A4 substrate showed that fulvestrant does not inhibit CYP3A4.
• Palbociclib and LHRH agonists: when fulvestrant is combined with palbociclib, the palbociclib SmPC must be read as well. Pre- and perimenopausal women need an LHRH agonist alongside the combination.
• Anticoagulants: because fulvestrant is injected into muscle, use it with caution in patients taking anticoagulant treatment, and in those with bleeding diatheses or thrombocytopenia.
• Oestradiol blood tests: because fulvestrant is structurally similar to oestradiol, it may interfere with antibody-based oestradiol assays and cause falsely raised results.

Fulvestrant is a prescription medicine for breast cancer that is injected by a healthcare professional. Each 500 mg dose is given as two consecutive 5 mL (250 mg) injections by slow intramuscular injection, one in each buttock (gluteal area), taking 1–2 minutes per injection. Caution is needed at the dorsogluteal site because the sciatic nerve lies close beneath it. Detailed administration instructions are in section 6.6 of the SmPC; each pack contains safety needles for the syringes.

Recommended Dose

• 500 mg (two 250 mg/5 mL injections) at intervals of one month, with an additional 500 mg dose two weeks after the initial dose. This applies to adult women, including the elderly.
• In combination with palbociclib: the fulvestrant dose is the same; see the palbociclib SmPC for its dose. Before the combination starts, and throughout treatment, pre- or perimenopausal women should be treated with an LHRH agonist according to local clinical practice.

Dose Adjustments

The SmPC gives no schedule of dose reductions for side effects. No dose adjustment is needed when fulvestrant is taken with CYP3A4 inhibitors or inducers.

Special Populations

• Elderly: the usual adult dose applies.
• Renal impairment: no dose adjustment in mild to moderate impairment. Safety and efficacy have not been evaluated in severe impairment (creatinine clearance below 30 mL/min), so caution is recommended.
• Hepatic impairment: no dose adjustment in mild to moderate impairment, but exposure may be increased, so use with caution. There are no data in severe hepatic impairment, which is a contraindication.
• Children and adolescents: safety and efficacy from birth to 18 years have not been established, no dose can be recommended, and fulvestrant is not recommended in this group.

Liver and Kidney Impairment

Use fulvestrant with caution in mild to moderate hepatic impairment and in severe renal impairment (creatinine clearance below 30 mL/min). Severe hepatic impairment is a contraindication.

Bleeding Disorders and Anticoagulants

Because of the intramuscular route, fulvestrant should be used with caution in patients with bleeding diatheses or thrombocytopenia, and in those taking anticoagulant treatment.

Thromboembolism

Thromboembolic events are common in women with advanced breast cancer and were seen in clinical studies of fulvestrant. This should be considered when prescribing for patients at risk.

Nerve Events at the Injection Site

Sciatica, neuralgia, neuropathic pain and peripheral neuropathy have been reported after injection. Take particular care at the dorsogluteal injection site because of the underlying sciatic nerve.

Bone Health

There are no long-term data on the effect of fulvestrant on bone. Because of its mechanism of action, there is a potential risk of osteoporosis.

Critical Visceral Disease

The efficacy and safety of fulvestrant, alone or with palbociclib, have not been studied in patients with critical visceral disease.

Laboratory Tests

Fulvestrant may interfere with antibody-based oestradiol assays and give falsely raised oestradiol levels.

Pregnancy, Breastfeeding and Fertility

• Contraception: patients of childbearing potential should use effective contraception during treatment and for 2 years after the last dose.
• Pregnancy: contraindicated. Fulvestrant crossed the placenta in rats and rabbits after single intramuscular doses, and animal studies showed reproductive toxicity, including more foetal abnormalities and deaths. If pregnancy occurs during treatment, the patient must be told about the potential hazard to the foetus and the risk of pregnancy loss.
• Breastfeeding: must be stopped during treatment, and use during lactation is contraindicated. Fulvestrant passes into the milk of lactating rats; it is not known whether it passes into human milk.
• Fertility: the effects of fulvestrant on human fertility have not been studied.

Ethanol, Benzyl Alcohol and Benzyl Benzoate

Each syringe contains 10% w/v ethanol, up to 500 mg per injection, equivalent to 12 mL of beer or 5 mL of wine. This may be harmful for people with alcoholism and should be taken into account in high-risk groups such as patients with liver disease or epilepsy. Benzyl alcohol (500 mg) may cause allergic reactions. The syringe also contains benzyl benzoate (750 mg).

Effect on Driving

Fulvestrant has no or negligible influence on the ability to drive or use machines. Asthenia is reported very commonly, so patients who experience it should take care when driving or operating machinery.

Store and transport the pre-filled syringes in a refrigerator at 2–8 °C, in the original package to protect them from light. Because it is a refrigerated product, fulvestrant must stay in a cold chain during transport and storage until it reaches the clinic.

Temperature excursions outside 2–8 °C should be limited. Avoid storage above 30 °C, and do not exceed 28 days where the average storage temperature is below 25 °C (but above 2–8 °C). After an excursion, return the product immediately to the refrigerator. Excursions have a cumulative effect on quality, and the 28-day limit must not be exceeded over the whole shelf life. Exposure to temperatures below 2 °C does not damage the product provided it is not stored below −20 °C.

4 years when stored as above. Temperature excursions count towards a single cumulative 28-day allowance over the 4-year shelf life. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist treating breast cancer. Fulvestrant is injected by a healthcare professional, so it is supplied to the hospital or clinic that administers it, in cold-chain delivery at 2–8 °C. Packs hold one or two 5 mL pre-filled syringes with safety needles; not all pack sizes may be marketed.