Eranfu

Solution for injection.
Fulvestrant Injection is a clear, colorless to yellow, viscous liquid free from visible particulate matter, presented in 5.0 mL Type-I glass syringe with OVS tip cap.
Each 5 mL of Prefilled syringe contains Fulvestrant USP 250 mg, Alcohol (Ethanol, 96%), Benzyl alcohol, Benzyl benzoate and Castor oil.

Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Fulvestrant is a competitive estrogen receptor (ER) antagonist with an affinity comparable to estradiol. Fulvestrant blocks the trophic actions of estrogens without any partial agonist (estrogen-like) activity. The mechanism of action is associated with down-regulation of estrogen receptor protein levels.
Clinical trials in postmenopausal women with primary breast cancer have shown that Fulvestrant significantly down-regulates ER protein in ER positive tumors compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen agonist effects. It has also been shown that Fulvestrant 500 mg down-regulates ER and the proliferation marker Ki67, to a greater degree than Fulvestrant 250 mg in breast tumors in postmenopausal neo-adjuvant 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 [35.3%] 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-glucoronide metabolites) are either less active or exhibit similar activity to Fulvestrant in anti-estrogen 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 feces, 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_1/2) 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 III 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.
Pediatric 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. The pediatric 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.

Fulvestrant is indicated for the: Treatment of hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy.
Treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy.
Treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after endocrine therapy.

Posology: Adult females (including 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.
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.
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 in caution in these patients. There are no data in patients with severe hepatic impairment.
Pediatric population: The safety and efficacy of fulvestrant in children from birth to 18 years of age have not been established.
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 (gluteal area). Caution should be taken if injecting fulvestrant at the dorsogluteal site due to the proximity of the underlying sciatic nerve.
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 at the dorsogluteal injection site.
Warning - Do not autoclave safety needle (SurGuard3 Safety Hypodermic Needle) before use. Hands must remain behind the needle at all times during use and disposal.
For each syringe: Remove glass syringe barrel from tray and check that it is not damaged.
Peel open the safety needle outer packaging.
Parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration.
Hold the syringe upright on the ribbed part. With the other hand, take hold of the cap and carefully tilt back and forth until the cap disconnects and can be pulled off, do not twist.
Remove the cap in a straight upward direction. To maintain sterility do not touch the syringe tip.
Step 1: Tighten the syringe to the needle using aseptic technic. Grip the base of the needle, not the safety sheath, push and turn the syringe clockwise.
Step 2: Move the safety sheath away from the needle and toward the syringe barrel to the angle, prior to removing the needle cap. Perform injection procedure according to established technic.
(Note: The needle "bevel up" position is oriented to the position of the safety sheath.)
Step 3: After the injection procedure, use a one-handed technic to activate the safety mechanism using any of the three (3) methods: Finger Activation or Thumb Activation or Surface Activation.
(Activation is verified by an audible and/or tactile "click", and can be visually confirmed.)
Step 4: Visually confirm that the safety sheath is fully engaged.
Pre-filled syringes are for single use only.
Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.

There is no human experience of overdose. Animal studies suggest that no effects other than those related directly or indirectly to anti-estrogenic activity were evident with higher doses of Fulvestrant. If overdose occurs, symptomatic supportive treatment is recommended.

Hypersensitivity to the active substance or to any of the other excipients.
Pregnancy and lactation.
Severe hepatic impairment.

Fulvestrant should be used with caution in patients with mild to moderate hepatic impairment.
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 trials with Fulvestrant. 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 when administering Fulvestrant at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve.
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.
Interference with estradiol antibody assays: Due to the structural similarity of Fulvestrant and estradiol, Fulvestrant may interfere with antibody based-estradiol assays and may result in falsely increased levels of estradiol.
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.

Women of childbearing potential: Patients of child-bearing potential should be advised to use effective contraception while on treatment.
Pregnancy: Fulvestrant is contraindicated in pregnancy. 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 fetal abnormalities and deaths. If pregnancy occurs while taking Fulvestrant, the patient must be informed of the potential hazard to the fetus 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.
Fertility: The effects of Fulvestrant on fertility in humans has not been studied.

This section provides information based on all adverse reactions from clinical trials, post-marketing studies or spontaneous reports. 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 Fulvestrant 500 mg treatment group in pooled safety analyses of the CONFIRM (Study D6997C00002), FINDER 1 (Study D6997C00004), FINDER 2 (Study D6997C00006) and NEWEST (Study D6997C00003) studies that compared Fulvestrant 500 mg with Fulvestrant 250 mg. The frequencies in the following table were based on all reported events, regardless of the investigator assessment of causality.
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. (See table.)

Click on icon to see table/diagram/image

A clinical interaction study with Midazolam (substate 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 incompatibility studies, this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2° to 8°C). Do not freeze.
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.

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