Fulvestrant Sandoz

Fulvestrant.

Each pre-filled syringe with 5 ml solution for injection contains 250 mg fulvestrant.
Excipients/Inactive Ingredients: Ethanol (96%), Benzyl alcohol, Benzyl benzoate, Castor oil.

Pharmacotherapeutic group: Endocrine therapy, hormone antagonists and related agents, anti-estrogens. ATC code: L02BA03.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity comparable to oestradiol. Fulvestrant blocks the trophic actions of oestrogens without any partial agonist (oestrogen-like) activity. The mechanism of action is associated with down-regulation of oestrogen receptor protein levels.
Clinical trials in postmenopausal women with primary breast cancer have shown that fulvestrant significantly down-regulates ER protein in ER positive tumours compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic oestrogen agonist effects. It has also been shown that fulvestrant 500 mg downregulates ER and the proliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal neoadjuvant setting.
Pharmacokinetics: Absorption: After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (C_max) are reached after about 5 days. Administration of fulvestrant 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng.days/ml, C_max 25.1 [35.1%] ng/ml, C_min 16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose proportional in the dose range 50 to 500 mg.
Distribution: Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state (Vd_ss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.
Biotransformation: The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids. Identified metabolites (includes 17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide metabolites) are either less active or exhibit similar activity to fulvestrant in anti-oestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant; however, non-P450 routes appear to be more predominant in vivo. In vitro data suggest that fulvestrant does not inhibit CYP450 isoenzymes.
Elimination: Fulvestrant is eliminated mainly in metabolised form. The major route of excretion is via the faeces, with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 11±1.7 ml/min/kg, suggesting a high hepatic extraction ratio. The terminal half-life (t_½) after intramuscular administration is governed by the absorption rate and was estimated to be 50 days.
Special populations: In a population pharmacokinetic analysis of data from phase 3 studies, no difference in fulvestrant's pharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) or race.
Renal impairment: Mild to moderate impairment of renal function did not influence the pharmacokinetics of fulvestrant to any clinically relevant extent.
Hepatic impairment: The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical trial conducted in subjects with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of a shorter duration intramuscular injection formulation was used. There was up to about 2.5-fold increase in AUC in subjects with hepatic impairment compared to healthy subjects. In patients administered fulvestrant, an increase in exposure of this magnitude is expected to be well tolerated. Subjects with severe hepatic impairment (Child-Pugh class C) were not evaluated.
Paediatric population: The pharmacokinetics of fulvestrant has been evaluated in a clinical trial conducted in 30 girls with Progressive Precocious Puberty associated with McCune Albright Syndrome (see Dosage & Administration). The paediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of fulvestrant. The geometric mean (standard deviation) steady state trough concentration (C_min,ss) and AUC_ss was 4.2 (0.9) ng/ml and 3680 (1020) ng*hr/ml, respectively. Although the data collected were limited, the steady-state trough concentrations of fulvestrant in children appear to be consistent with those in adults.
Toxicology: Preclinical safety data: The acute toxicity of fulvestrant is low.
Fulvestrant and other formulations of fulvestrant were well tolerated in animal species used in multiple dose studies. Local reactions, including myositis and granulomata at the injection site were attributed to the vehicle but the severity of myositis in rabbits increased with fulvestrant, compared to the saline control. In toxicity studies with multiple intramuscular doses of fulvestrant in rats and dogs, the anti-estrogenic activity of fulvestrant was responsible for most of the effects seen, particularly in the female reproductive system, but also in other organs sensitive to hormones in both sexes. Arteritis involving a range of different tissues was seen in some dogs after chronic (12 months) dosing.
In dog studies following oral and intravenous administration, effects on the cardiovascular system (slight elevations of the S-T segment of the ECG [oral], and sinus arrest in one dog [intravenous]) were seen. These occurred at exposure levels higher than in patients (C_max >15 times) and are likely to be of limited significance for human safety at the clinical dose.
Fulvestrant showed no genotoxic potential.
Fulvestrant showed effects upon reproduction and embryo/foetal development consistent with its anti-estrogenic activity, at doses similar to the clinical dose. In rats, a reversible reduction in female fertility and embryonic survival, dystocia and an increased incidence of foetal abnormalities including tarsal flexure were observed. Rabbits given fulvestrant failed to maintain pregnancy. Increases in placental weight and post-implantation loss of foetuses were seen. There was an increased incidence of foetal variations in rabbits (backwards displacement of the pelvic girdle and 27 pre-sacral vertebrae).
A two-year oncogenicity study in rats (intramuscular administration of fulvestrant) showed increased incidence of ovarian benign granulosa cell tumours in female rats at the high dose, 10 mg/rat/15 days and an increased incidence of testicular Leydig cell tumours in males. In a two-year mouse oncogenicity study (daily oral administration) there was an increased incidence of ovarian sex cord stromal tumours (both benign and malignant) at doses of 150 and 500 mg/kg/day. At the no-effect level for these findings, systemic exposure levels (AUC) were, in rats, approximately 1.5-fold the expected human exposure levels in females and 0.8-fold in males, and in mice, approximately 0.8-fold the expected human exposure levels in both males and females. Induction of such tumours is consistent with pharmacology-related endocrine feedback alterations in gonadotropin levels caused by anti-oestrogens in cycling animals. Therefore these findings are not considered to be relevant to the use of fulvestrant in postmenopausal women with advanced breast cancer.

Fulvestrant is indicated as monotherapy for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant antiestrogen therapy, or disease progression on therapy with an antiestrogen.
Fulvestrant is indicated in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in woman who have received prior endocrine therapy.
In pre- or perimenopausal women, the combination treatment with palbociclib should be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

Posology: Adult females (including the elderly): The recommended dose is 500 mg at intervals of one month, with an additional 500 mg dose given two weeks after the initial dose.
[Fulvestrant in indication "combination with palbociclib"]: When fulvestrant is used in combination with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.
Prior to the start of treatment with the combination of fulvestrant plus palbociclib, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.
[Fulvestrant in all indications]: Special population: Renal impairment: No dose adjustments are recommended for patients with mild to moderate renal impairment (creatinine clearance ≥30 ml/min). Safety and efficacy have not been evaluated in patients with severe renal impairment (creatinine clearance <30 ml/min), and, therefore, caution is recommended in these patients (see Precautions).
Hepatic impairment: No dose adjustments are recommended for patients with mild to moderate hepatic impairment. However, as fulvestrant exposure may be increased, fulvestrant should be used with caution in these patients. There are no data in patients with severe hepatic impairment (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of fulvestrant in children from birth to 18 years of age have not been established.
Fulvestrant is not indicated for use in children. The European Medicines Agency has waived the obligation to submit the results of studies with fulvestrant in all subsets of the paediatric population in breast cancer.
Method of administration: Fulvestrant should be administered as two consecutive 5 ml injections by slow intramuscular injection (1-2 minutes/injection), one in each buttock.
Caution should be taken if injecting fulvestrant at the dorsogluteal site due to the proximity of the underlying sciatic nerve.
For detailed instructions for administration see Special precautions for disposal and other handling under Cautions for Usage.
For instructions of the medicinal product before administration see Special precautions for disposal and other handling under Cautions for Usage.

There are isolated reports of overdose with fulvestrant in humans.
If overdose occurs, symptomatic supportive treatment is recommended.
Animal studies suggest that no effects other than those related directly or indirectly to anti-estrogenic activity were evident with higher doses of fulvestrant (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Hypersensitivity to the active substance or to any of the excipients.
Pregnancy and lactation (see Use in Pregnancy & Lactation).
Severe hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).

Fulvestrant should be used with caution in patients with mild to moderate hepatic impairment (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics under Actions).
Fulvestrant should be used with caution in patients with severe renal impairment (creatinine clearance less than 30 ml/min).
Due to the intramuscular route of administration, fulvestrant should be used with caution if treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant treatment.
Thromboembolic events are commonly observed in women with advanced breast cancer and have been observed in clinical studies with fulvestrant (see Adverse Reactions). This should be taken into consideration when prescribing fulvestrant to patients at risk.
Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve (see Dosage & Administration and Adverse Reactions).
There are no long-term data on the effect of fulvestrant on bone. Due to the mechanism of action of fulvestrant, there is a potential risk of osteoporosis.
The efficacy and safety of fulvestrant (either as monotherapy or in combination with palbociclib) have not been studied in patients with critical visceral disease.
[Fulvestrant in indication "combination with palbociclib"]: When fulvestrant is combined with palbociclib, please also refer to the Summary of Product Characteristics of palbociclib.
[Fulvestrant in all indications]: Interference with oestradiol antibody assays: Due to the structural similarity of fulvestrant and oestradiol, fulvestrant may interfere with antibody based-oestradiol assays and may result in falsely increased levels of oestradiol.
Effects on ability to drive and use machines: Fulvestrant has no or negligible influence on the ability to drive or use machines. However, since asthenia has been reported very commonly with fulvestrant, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.
Use in Children: Fulvestrant is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see Dosage & Administration).

Women of childbearing potential: Patients of childbearing potential should use effective contraception during treatment with fulvestrant and for 2 years after the last dose.
Pregnancy: Fulvestrant is contraindicated in pregnancy (see Contraindications). Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and rabbit. Studies in animals have shown reproductive toxicity including an increased incidence of foetal abnormalities and deaths (see Pharmacology: Toxicology: Preclinical safety data under Actions). If pregnancy occurs while taking fulvestrant, the patient must be informed of the potential hazard to the foetus and potential risk for loss of pregnancy.
Breast-feeding: Breast-feeding must be discontinued during treatment with fulvestrant. Fulvestrant is excreted in milk in lactating rats. It is not known whether fulvestrant is excreted in human milk. Considering the potential for serious adverse reactions due to fulvestrant in breast-fed infants, use during lactation is contraindicated (see Contraindications).
Fertility: The effects of fulvestrant on fertility in humans has not been studied.

Summary of the safety profile: Monotherapy: This section provides information based on all adverse reactions from clinical studies, post-marketing studies or spontaneous reports. In the pooled dataset of fulvestrant monotherapy, the most frequently reported adverse reactions are injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP).
The following frequency categories for adverse drug reactions (ADRs) were calculated based on the fulvestrant 500 mg treatment group in pooled safety analyses of studies that compared fulvestrant 500 mg with fulvestrant 250 mg [CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006), and NEWEST (Study D6997C00003) studies], or from FALCON (Study D699BC00001) alone that compared fulvestrant 500 mg with anastrozole 1 mg. Where frequencies differ between the pooled safety analysis and FALCON, the highest frequency is presented. The frequencies in the following list were based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
The median duration of fulvestrant 500 mg treatment across the pooled dataset (including the studies mentioned previously plus FALCON) was 6.5 months.
List of adverse reactions: Adverse reactions listed as follows are classified according to frequency and System Organ Class (SOC).
Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within each frequency grouping adverse reactions are reported in order of decreasing seriousness.
Infections and infestations: Common: Urinary tract infections.
Blood and lymphatic system disorders: Common: Reduced platelet count^e.
Immune system disorders: Very common: Hypersensitivity reactions^e.
Uncommon: Anaphylactic reactions.
Metabolism and nutrition disorders: Common: Anorexia^a.
Nervous system disorders: Common: Headache.
Vascular disorders: Very common: Hot flushes^e.
Common: Venous thromboembolism^a.
Gastrointestinal disorders: Very common: Nausea.
Common: Vomiting, diarrhoea.
Hepatobiliary disorders: Very common: Elevated hepatic enzymes (ALT, AST, ALP)^a.
Common: Elevated bilirubin^a.
Uncommon: Hepatic failure^c,f, hepatitis^f, elevated gamma-GT^f.
Skin and subcutaneous tissue disorders: Very common: Rash^e.
Musculoskeletal and connective tissue disorders: Very common: Joint and musculoskeletal pain^d.
Common: Back pain^a.
Reproductive system and breast disorders: Common: Vaginal haemorrhage^e.
Uncommon: Vaginal moniliasis^f, leukorrhoea^f.
General disorders and administration site conditions: Very common: Asthenia^a, injection site reactions^b.
Common: Neuropathy peripheral^e, sciatica^e.
Uncommon: Injection site haemorrhage^f, injection site haematoma^f, neuralgia^c,f.
^a Includes adverse drug reactions for which the exact contribution of fulvestrant cannot be assessed due to the underlying disease.
^b The term injection site reactions does not include the terms injection site haemorrhage, injection site haematoma, sciatica, neuralgia and neuropathy peripheral.
^c The event was not observed in major clinical studies (CONFIRM, FINDER 1, FINDER 2, NEWEST).
The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate. This is calculated as 3/560 (where 560 is the number of patients in the major clinical studies), which equates to a frequency category of 'uncommon'.
^d Includes: arthralgia, and less frequently musculoskeletal pain, myalgia and pain in extremity.
^e Frequency category differs between pooled safety dataset and FALCON.
^f ADR was not observed in FALCON.
Description of selected adverse reactions: The descriptions included as follows are based on the safety analysis set of 228 patients who received at least one (1) dose of fulvestrant and 232 patients who received at least one (1) dose of anastrozole, respectively in the Phase 3 FALCON study.
Joint and musculoskeletal pain: In the FALCON study, the number of patients who reported an adverse reaction of joint and musculoskeletal pain was 65 (31.2%) and 48 (24.1%) for fulvestrant and anastrozole arms, respectively. Of the 65 patients in the fulvestrant arm, 40% (26/65) of patients reported joint and musculoskeletal pain within the first month of treatment, and 66.2% (43/65) of patients within the first 3 months of treatment. No patients reported events that were CTCAE Grade ≥3 or that required a dose reduction, dose interruption, or discontinued treatment due to these adverse reactions.
[Fulvestrant in indication "combination with palbociclib"]: Combination therapy with palbociclib: The overall safety profile of fulvestrant when used in combination with palbociclib is based on data from 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer in the randomised PALOMA3 study (see Pharmacology: Pharmacodynamics under Actions). The most common (≥20%) adverse reactions of any grade reported in patients receiving fulvestrant in combination with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea, and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions were neutropenia, leukopenia, anaemia, infections, AST increased, thrombocytopenia, and fatigue.
The table as follows reports the adverse reactions from PALOMA3.
Median duration of exposure to fulvestrant was 11.2 months in the fulvestrant + palbociclib arm and 4.9 months in the fulvestrant + placebo arm. Median duration of exposure to palbociclib in the fulvestrant + palbociclib arm was 10.8 months. (See table.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Neutropenia: In patients receiving fulvestrant in combination with palbociclib in the PALOMA3 study, neutropenia of any grade was reported in 287 (83.2%) patients, with Grade 3 neutropenia being reported in 191 (55.4%) patients, and Grade 4 neutropenia being reported in 37 (10.7%) patients. In the fulvestrant + placebo arm (n=172), neutropenia of any grade was reported in 7 (4.1%) patients, with Grade 3 neutropenia reported in 1 (0.6%) patient. There were no reports of Grade 4 neutropenia in the fulvestrant + placebo arm.
In patients receiving fulvestrant in combination with palbociclib, the median time to first episode of any grade neutropenia was 15 days (range: 13-317) and the median duration of Grade ≥3 neutropenia was 7 days. Febrile neutropenia has been reported in 0.9% patients receiving fulvestrant in combination with palbociclib.

A clinical interaction study with midazolam (substrate of CYP3A4) demonstrated that fulvestrant does not inhibit CYP3A4. Clinical interaction studies with rifampicin (inducer of CYP3A4) and ketoconazole (inhibitor of CYP3A4) showed no clinically relevant change in fulvestrant clearance.
Dose adjustment is therefore not necessary in patients who are receiving fulvestrant and CYP3A4 inhibitors or inducers concomitantly.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: Instructions for administration: Administer the injection according to the local guidelines for performing large volume intramuscular injections.
NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering [Fulvestrant - parenteral dosage forms] at the dorsogluteal injection site (see Precautions).
Warning: Do not autoclave safety needle before use. Hands must remain behind the needle at all times during use and disposal.
Syringes are supplied with safety needle BD SafetyGlide.
Instructions for safety needle BD SafetyGlide: For each of the two syringes: Carefully remove the needle and syringe from the packaging.
Remove the protective cap from the tip of the syringe barrel.
Peel open the safety needle (BD SafetyGlide) outer packaging. Attach the safety needle to the Luer-Lock.
Twist to lock the needle to the Luer connector. Twist until firmly seated.
Pull shield straight off needle to avoid damaging needle point.
Remove needle sheath.
While holding the syringe with the needle pointing upward, gently push in the plunger until the medicine is up to the top of the syringe. There should be no air within the barrel.
Administer intramuscularly slowly (1-2 minutes/injection) into the buttock. For user convenience, the needle bevel-up position is oriented to the lever arm.
After injection, immediately apply a single-finger stroke to the activation assisted lever arm to activate the shielding mechanism.
NOTE: Activate away from self and others. Listen for click and visually confirm needle tip is fully covered.
Disposal: Pre-filled syringes are for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator (2°C - 8°C).
Store the pre-filled syringe in the original package in order to protect from light.

Cancer Hormone Therapy

L02BA03 - fulvestrant ; Belongs to the class of anti-estrogens. Used in treatment of neoplastic diseases.

S