Each 5 mL of prefilled syringe contains: (See Table 1.)
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Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity comparable to estradiol. 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.
Pharmacokinetics: Absorption: After administration of fulvestrant long-acting intramuscular injection, fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days.
Distribution: Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady-state (VDss) 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.
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 (t½) after intramuscular administration is governed by the absorption rate and was estimated to be 50 days.
Fulvestrant is indicated for the treatment of: estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy; estrogen receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women with disease relapse on or after adjuvant endocrine therapy, or disease progression on endocrine therapy.
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 with caution in these patients. There are no data in patients with severe hepatic impairment.
Paediatric population: Fulvestrant is not recommended for use in children or adolescents, as safety and efficacy have not been established in this age group.
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 of the two syringes: Remove glass syringe barrel from blister tray and check that it is not damaged.
Break the seal of the white plastic cover on the syringe Luer connector Luer-Lok to remove the cover with the attached.
Peel open the safety needle (Terumo SurGuard) outer packaging.
Attach the safety needle to the Luer-Lok.
Twist until firmly seated.
Twist to lock the needle to the Luer connector.
Transport filled syringe to point of administration.
Move the safety sheath away from the needle and toward the syringe barrel to the angle shown, prior to removing the needle cap.
Parenteral solutions must be inspected visually for particulate matter and discolouration prior to administration.
Remove the needle cap.
Expel excess gas from the syringe.
Administer intramuscularly slowly (1-2 minutes/injection) into the buttock. For user convenience, the needle bevel-up position is oriented to the lever arm.
Use the finger grip if necessary.
After injection, use a one-handed technique to activate the safety mechanism using any of the two methods (Activation is verified by an audible and/or tactile "click" and can be visually confirmed.)
NOTE: Activate away from self and others. Listen for click and visually confirm needle tip is fully covered Finger Activation; Thumb Activation; Visual Confirmation.
Disposal: Pre-filled syringes are for single use only.
Any unused medicinal product or waste should be disposed of in accordance with local requirements.
There are isolated reports of overdose with fulvestrant in humans. Animal studies suggest that no effects other than those related directly or indirectly to anti-oestrogenic 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.
As this preparation contains benzyl alcohol, its use should be avoided in children under two years of age. Not to be used in neonates.
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. 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.
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 child bearing potential: Patients of child-bearing potential should be advised to use effective contraception while on treatment.
Pregnancy: Fulvestrant is contraindicated in pregnancy. 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. 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.
The most frequently reported adverse reactions are injection site reactions, asthenia, nausea, and increased hepatic enzymes (ALT, AST, ALP). (See Table 2.)
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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 incompatibility studies, this medicinal product must not be mixed with other medicinal products.
Store in refrigerator at 2°C to 8°C, Do not freeze.
Store the pre-filled syringe in the original package, in order to protect from light.
Shelf-Life: 24 Months.
L02BA03 - fulvestrant ; Belongs to the class of anti-estrogens. Used in treatment of neoplastic diseases.
Soln for inj (pre-filled syringe) 250 mg/5 mL (clear, colorless to yellow, viscous liquid free from visible particulate matter) x 2's.