Professional Drug Information > Faslodex

Fulvestrant (Systemic)

VA CLASSIFICATION
Primary: AN500

Commonly used brand name(s): Faslodex.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antineoplastic—

Indications

Accepted

Carcinoma, breast (treatment)—Fulvestrant is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. ^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Estrogen receptor antagonist ^{01}
Molecular weight—
    606.77 ^{01}

Mechanism of action/Effect:

Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to estradiol. Fulvestrant down regulates the estrogen receptors (ER) protein in human breast cancer cells. ^{01}

Clinical studies demonstrate that increasing down regulation of ER with increasing dose. This down regulation is associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-related protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation. ^{01}

Vol_D

Steady state—3 to 5 liters per kilogram; distribution is extensive and rapid; largely extravascular. ^{01}

Protein binding:

Very high (99%); bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions appear to be the major binding components. ^{01}

Biotransformation:

Metabolism appears to involve combinations of a number of pathways, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulfate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulfoxide. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown. ^{01}

Half-life:

Approximately 40 days ^{01}

Steady-state concentration:

Following administration of 250 milligrams of fulvestrant intramuscularly every month—after 3 to 6 doses. ^{01}

Peak plasma concentration:

Following an intramuscular injection—approximately 7 days; concentration is maintained for at least one month. ^{01}

Elimination:
    Rapidly cleared by hepatobiliary route at a rate of about 10.5 milliliters plasma per minute per kilogram. ^{01}
    Fecal—approximately 90% ^{01}
    Renal—negligible (<1%) ^{01}

Pharmacokinetic Profile

The following table represents the mean pharmacokinetic parameters after intramuscular administration of 250 milligrams of fulvestrant

Pharmacokinetic Parameters	Cmax (ng/mL)	AUC (ng.d/mL)	CL (mL/min)
Single dose	8.5	131	690
Multiple dose (Steady-state)	15.8	328

^{01}


Precautions to Consider

Tumorigenicity

Studies in rats have found an increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors. ^{01}

Mutagenicity

Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests. ^{01}

Pregnancy/Reproduction
Fertility—
In female rats, fulvestrant administered at doses ³ 0.01 mg per kg per day (approximately one-hundredth of the human recommended dose based on body surface area [BSA] for two weeks prior to and for one week following mating) caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in animals dosed at 0.001 mg per kg per day (approximately one-thousandth of the human dose based on BSA). ^{01}

The effects of fulvestrant on the fertility of male animals has not been studied. In a 6-month toxicology study, male rats treated with doses larger than the human recommended equivalent resulted in loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. ^{01}

Pregnancy—
Fulvestrant is contraindicated in pregnant women. Women of childbearing potential should be advised not to become pregnant while receiving fulvestrant. If the patient becomes pregnant while receiving fulvestrant, the patient should be apprised of the potential hazard to the fetus, or potential risk for loss of the pregnancy. ^{01}

Fulvestrant crosses the placenta and has been shown to cause fetal harm in rats and rabbits. ^{01} Risk benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective.

In studies in rats, intramuscular doses of fulvestrant caused an increased incidence of fetal abnormalities and death. Similarly, rabbits failed to maintain pregnancy and the fetuses showed an increased incidence of skeletal variations. ^{01}

FDA Pregnancy Category D ^{01}

Breast-feeding

It is not known whether fulvestrant is distributed into human breast milk. However, fulvestrant is distributed into the milk of lactating rats. Because of the potential for serious adverse reactions from fulvestrant in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into consideration the importance of the drug to the mother. ^{01}

Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of fulvestrant in the pediatric population. Safety and efficacy have not been established. ^{01}


Geriatrics


Appropriate studies on the relationship of age to the effects of fulvestrant have not been performed in the geriatric population. No geriatrics-specific problems have been identified. However, when tumor response was considered by age, objective response rates were greater in patients under 65 years of age (complete response 24%; partial response 22%) than in patients 65 years of age and older (complete response 16%; partial response 11%). ^{01}

There was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years) in patients with breast cancer. ^{01}


Pharmacogenetics

No differences in fulvestrant pharmacokinetics were observed due to race, gender, or menopausal status. ^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants    (may increase the risk of bleeding or bruising associated with the intramuscular administration of fulvestrant ^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Bleeding diathesis or
» Thrombocytopenia    (these conditions may increase the risk of bleeding or bruising associated with the intramuscular administration of fulvestrant ^{01})


» Hepatic impairment, moderate to severe    (safety and efficacy have not been evaluated in patients with moderate to severe hepatic impairment ^{01})


» Hypersensitivity to fulvestrant ^{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Pregnancy testing    (recommended before starting treatment with fulvestrant; ^{01} women of childbearing potential should be asked about pregnancy status periodically during treatment with fulvestrant and advised not to become pregnant while receiving fulvestrant)






Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Peripheral edema^{01} (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet; unusual weight gain or loss)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain ^{01}
    
anorexia ^{01} (loss of appetite; weight loss)
    
asthenia ^{01} (lack or loss of strength)
    
back pain ^{01}
    
bone pain ^{01}
    
chest pain ^{01}
    
constipation^{01}
    
cough, increased ^{01}
    
depression ^{01} (discouragement; feeling sad or empty; irritability; lack of appetite; loss of interest or pleasure; tiredness; trouble concentrating; trouble sleeping)
    
diarrhea ^{01}
    
dizziness ^{01}
    
dyspnea ^{01} (shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
    
fever ^{01}
    
flu syndrome ^{01} (chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
    
headache ^{01}
    
injection site pain ^{01}
    
insomnia ^{01} ( sleeplessness; trouble sleeping; unable to sleep)
    
nausea ^{01}
    
pain ^{01}
    
paresthesia ^{01} (burning, crawling, itching, numbness, prickling, "pins and needles" , or tingling feelings)
    
pelvic pain ^{01}
    
pharyngitis ^{01} (body aches or pain; congestion; cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)
    
skin rash ^{01}
    
vasodilation ^{01} (feeling of warmth or heat; flushing or redness of skin, especially on face and neck; headache; feeling faint, dizzy, or light-headedness; sweating)
    
urinary tract infection ^{01} (bladder pain; bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate; lower back or side pain)
    
vomiting ^{01}

Incidence less frequent
    
Accidental injury ^{01}
    
anemia ^{01} (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness)
    
anxiety ^{01} (fear; nervousness )
    
arthritis ^{01} ( pain, swelling, or redness in joints; muscle pain or stiffness; difficulty in moving)
    
sweating ^{01}

Incidence rare
    
Leukopenia ^{01} (black, tarry stools; chest pain; chills; cough; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)
    
myalgia ^{01} (joint pain; swollen joints; muscle aching or cramping; muscle pains or stiffness; difficulty in moving)
    
thromboembolic phenomena ^{01} (pain in chest, groin, or legs, especially the calves; difficulty breathing; severe, sudden headache; slurred speech; sudden, unexplained shortness of breath; sudden loss of coordination; sudden, severe weakness or numbness in arm or leg; vision changes)
    
vaginal bleeding ^{01}
    
vertigo (dizziness or lightheadedness; feeling of constant movement of self or surroundings; sensation of spinning )





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
There is no clinical experience with overdosage in humans. No adverse effects were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations that were approximately 10 to 15 times those seen after intramuscular injection. Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity following intramuscular administration of fulvestrant at doses higher than recommended in humans. ^{01}

Treatment of overdose


Supportive care:
Treatment should be symptomatic and supportive. ^{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Fulvestrant (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Do not take fulvestrant during pregnancy. Fulvestrant crosses the placenta and has been shown to cause fetal harm in animals. Tell your physician immediately if pregnancy is suspected. Do not become pregnant while receiving fulvestrant.





Breast-feeding—It is not known whether fulvestrant is distributed into human breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether or not to discontinue nursing, taking into consideration the importance of the drug to the mother.





Use in the elderly—When tumor response was considered by age, objective response rates were greater in patients under 65 years of age.
Other medications, especially anticoagulants
Other medical problems, especially bleeding diathesis, thrombocytopenia, or moderate to severe hepatic impairment

Proper use of this medication
Importance of proper intramuscular use

Importance of proper handling and disposal of needles and syringes

» Proper dosing: Administer one dose each month, on the same day each month (e.g., first day of month).

Proper storage: Store in refrigerator. Protect from light by storing in the original carton until time of use.
If dosing schedule is once a month: administer missed dose as soon as possible; do not double doses or administer more often than one dose every 30 days.

Precautions while using this medication
» Regular visits to physician to check progress during therapy

» For women of reproductive age—Importance of not becoming pregnant while receiving fulvestrant


Side/adverse effects
Signs of potential side effects, especially peripheral edema


General Dosing Information
For the two 2.5-mL syringe package only, both syringes must be administered to receive the 250 mg recommended monthly dose. ^{01}

The injection should be administered slowly into the buttock. ^{01}
Using care in handling contaminated needles to avoid HIV (AIDS), HBV (Hepatitis) and other infectious diseases due to accidental needlesticks; not recapping or removing contaminated needles, unless there is no alternative or that such action is required by a specific medical procedure. ^{01}

Using a one-handed technique and activating away from self and others for greatest safety. ^{01}

Keeping hands behind the needle at all times during use and disposal and not autoclaving the needle. ^{01}

Discard syringe in an approved sharps collector in accordance with applicable regulations after single use. ^{01}


Parenteral Dosage Forms

FULVESTRANT INJECTION

Usual Adult Dose
Carcinoma, breast
Intramuscular, 250 mg once monthly as a single 5-mL injection or two concurrent 2.5-mL injections ^{01}


Note: Safety and efficacy of fulvestrant have not been evaluated in patients with moderate to severe hepatic impairment. No dosage adjustment is recommended in patients with mild hepatic impairment.^{01}
Mild hepatic impairment is defined as:   • alanine aminotransferase [ALT] concentration greater than the upper limit of normal (ULN) but less than two times the ULN or
   • any two of the following 3 parameters were between one and two times the ULN:   —aspartate aminotransferase [AST]
   —alkaline phosphatase
   —total bilirubin




Usual Pediatric Dose
Carcinoma, breast
Safety and efficacy have not been established. ^{01}


Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


250 mg of fulvestrant per 5-mL prefilled syringe (50 mg/mL) (Rx) [Faslodex (alcohol) (benzyl alcohol) (benzyl benzoate) ( castor oil)^{01}]


125 mg of fulvestrant per 2.5-mL prefilled syringe (50 mg/mL) (Rx) [Faslodex (contains two 5-mL prefilled syringes containing 2.5 mL) (alcohol) (benzyl alcohol) (benzyl benzoate) ( castor oil)^{01}]

Canada—
Not commercially available

Packaging and storage:
Store between 2 and 8°C (36 and 46°F). Protect from light by storing in the original carton until time of use. ^{01}

Auxiliary labeling:
   • For intramuscular (I.M.) use only
   • Refrigerate
   • Protect from light

Additional information:
See the manufacturer's package insert for instructions for intramuscular use, handling and disposal of fulvestrant injection. ^{01}

Developed: 01/21/2002

References

1. Product Information: Faslodex^®, fulvestrant (injection). AstraZeneca Pharmaceuticals, Wilmington, Delaware, (PI revised 07/2002) reviewed 12/2002.
   

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