COMMON TRADE NAME(S): FASLODEX®
CLASSIFICATION: hormonal agent, cytotoxic1
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Fulvestrant acts as an estrogen receptor (ER) antagonist, by competitively binding to estrogen receptors on tumour and other tissue targets, producing a nuclear complex that decreases DNA synthesis.2,3 Fulvestrant has no ER agonist activity.3
Fulvestrant significantly downregulates ER expression in ER positive tumours and also produces a significant decrease in progesterone receptor expression.3 Fulvestrant has demonstrated activity against tamoxifen-resistant breast cancers.4 Fulvestrant-resistant tumours may be cross-resistant to tamoxifen.3
PHARMACOKINETICS:
|
Oral Absorption |
poor2 |
|
Distribution |
extensive and rapid; peak plasma levels achieved after 7-9 days4; steady-state concentrations achieved within 3-6 months4; plasma levels maintained for at least 1 month2,4 |
|
cross blood brain barrier? |
no information found |
|
volume of distribution |
3-5 L/kg; suggests extravascular distribution |
|
plasma protein binding |
99%; primarily to VLDL, LDL and HDL lipoprotein fractions |
|
Metabolism |
extensive hepatic; several biotransformation pathways including oxidation, aromatic hydroxylation, and conjugation, similar to endogenous steroids |
|
active metabolite(s) |
yes |
|
inactive metabolite(s) |
yes |
|
Excretion |
rapid hepatic clearance; exposure and elimination primarily determined by rate of release from injection site |
|
urine |
<1% |
|
feces |
90% |
|
terminal half life2,4 |
~40 d |
|
clearance |
rate approximates hepatic blood flow (10.5 mL plasma/min/kg); mean clearance reduced 1.3 and 2.2- fold in patients with mild and moderate hepatic impairment respectively3 |
|
Sex |
no significant difference |
|
Elderly |
no significant difference |
|
Ethnicity |
no significant difference |
Adapted from standard reference3 unless specified otherwise.
USES:
|
Primary uses: |
Other uses: |
|
*Breast cancer |
|
*Health Canada approved indication
SPECIAL PRECAUTIONS:
Contraindicated in patients with a history of hypersensitivity reaction to fulvestrant or any of the excipients, including benzyl alcohol.3,4
Efficacy in premenopausal women has not been established4
Carcinogenicity: Increased incidence of benign ovarian granulosa cell tumours and testicular Leydig cell tumours in male and female rats, at doses approximating 1 to 5-fold the systemic exposure achieved in women.3
Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test.3 Fulvestrant is not clastogenic in mammalian in vitro and in vivo chromosome tests.3
Fertility: Effects upon reproduction, including a reversible reduction in fertility, have been demonstrated in rats and rabbits at doses similar to, or lower than typical human doses, on a mg/m2 basis.3 No information found regarding fertility in male animals receiving fulvestrant.3
Pregnancy: FDA Pregnancy Category D.2,4 There is positive evidence of human fetal risk,3 but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding is not recommended due to the potential secretion into breast milk.3 In rats, fulvestrant is distributed into milk at levels significantly higher than those in plasma.3
SIDE EFFECTS:
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.5
ORGAN SITE |
SIDE EFFECT |
|
Clinically important side effects are in bold, italics |
|
allergy/immunology |
hypersensitivity reactions (<1%); including angioedema and urticaria; typically occurs shortly after injection; angioedema occurring several days after injection has been reported in one case |
|
blood/bone marrow/
febrile neutropenia |
anemia (5%) |
|
leukopenia (<1%)2 |
|
cardiovascular (general) |
vasodilation (18%) |
|
constitutional symptoms |
asthenia (<23%); typically mild or moderate |
|
fever (6%) |
|
hot flashes (<24%)3,4,6 |
|
sweating (5%) |
|
dermatology/skin |
extravasation hazard: none7 |
|
injection site reactions (<10%); increased frequency (27%) when dose is divided into 2 injections; reaction includes mild transient pain and inflammation; may occur after prior uneventful injection and has been reported to develop into a systemic allergic response |
|
rash (<10%); typically mild |
|
gastrointestinal |
emetogenic potential: rare8 |
|
anorexia (<10%); typically mild |
|
constipation (13%) |
|
diarrhea (<12%); typically mild |
|
nausea (<26%); typically mild |
|
vomiting (<13%); typically mild |
|
hepatobiliary/pancreas |
elevated liver enzymes (<10%); typically < 2 x ULN |
|
infection |
urinary tract infections (<10%); typically mild |
|
lymphatics |
peripheral edema (9%) |
|
musculoskeletal |
arthritis (3%) |
|
neurology |
anxiety (5%) |
|
depression (6%) |
|
dizziness (7%) |
|
insomnia (7%) |
|
paresthesia (6%) |
|
pain |
abdominal pain (12%) |
|
back pain (14%) |
|
bone pain (16%) |
|
chest pain (7%) |
|
headache (<15%); typically mild |
|
injection site pain (11%) |
|
pain not otherwise specified (19%) |
|
pelvic pain (10%) |
|
pulmonary |
dyspnea (15%) |
|
increased cough (10%) |
|
pharyngitis (16%) |
|
sexual/reproductive function |
vaginal bleeding (<1%)2,4; typically occurs during the first 6 weeks of changing from existing hormonal therapy4 |
|
syndromes |
flu-like syndrome (7%) |
|
vascular |
thrombosis (<1%)2 |
Adapted from standard reference3 unless specified otherwise.
INTERACTIONS:
Although fulvestrant may be a minor substrate of CYP 3A4,2,3 dosage adjustment is not necessary when prescribed with CYP 3A4 inhibitors or inducers.3 In small clinical studies, ketoconazole and rifampicin were tested with fulvestrant and no pharmacokinetic interactions were noted.3 Fulvestrant does not significantly inhibit any of the major CYP P450 isoenzymes in vitro.3
SUPPLY AND STORAGE:
Injection: AstraZeneca Canada Inc. supplies fulvestrant as a 250 mg/5 mL long-acting, single-use, sterile solution in a pre-filled syringe. Selected non-medicinal ingredients: ethanol 96%, benzyl alcohol, benzyl benzoate, and castor oil. Store in original packaging, in the refrigerator.3 May be removed from the refrigerator and kept at room temperature or rolled gently between the hands before administration to ensure patient comfort.4
Additional information: The manufacturer’s prescribing information should be consulted for details on assembly and use of the safety needle.3,4
PARENTERAL ADMINISTRATION:
|
BCCA administration guideline noted in bold, italics |
|
Subcutaneous |
should not be used2 |
|
Intramuscular |
administer slowly into the gluteal muscle3 |
|
Direct intravenous |
should not be used2 |
|
Intermittent infusion |
no information found |
|
Continuous infusion |
no information found |
|
Intraperitoneal |
no information found |
|
Intrapleural |
no information found |
|
Intrathecal |
no information found |
|
Intra-arterial |
should not be used2 |
|
Intravesical |
no information found |
DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated.
Adults:
|
|
|
BCCA usual dose noted in bold, italics |
|
|
Cycle Length: |
|
|
Intramuscular: |
monthly: |
250 mg IM for one dose on day 1
(total dose per cycle 250 mg)
dose has been divided into two concurrent injections2-4 which may be administered bilaterally4; however, an increased incidence of injection site reactions have been reported3 |
|
|
|
|
|
Concurrent radiation: |
has been used5 |
|
|
|
|
|
Dosage in myelosuppression: |
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" |
|
|
|
|
|
Dosage in renal failure3: |
Creatinine clearance (mL/min) |
Dose |
|
|
>30 |
100% |
|
|
<30 |
use with caution; safety and effectiveness have not been established; no dosing details found |
|
|
Calculated creatinine clearance = N* x (140 – Age) x weight in kg
Serum Creatinine in µmol/L
* For males N=1.23; for females N=1.04
|
|
Dosage in hepatic failure: |
- mild to moderate impairment (Child-Pugh A and B): no adjustment required3
- severe impairment (Child-Pugh C): use with caution; safety and effectiveness have not been established3; no dosing details found
|
|
|
|
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Dosage in dialysis: |
no information found |
|
|
|
|
|
|
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Children:
|
|
safety and effectiveness have not been established3 |
References:
1. National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40.
2. Rose BD editor. Fulvestrant. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate®; 2008.
3. AstraZeneca Canada Inc. FASLODEX® Injection Product Monograph. Mississauga, Ontario; 11 December 2006.
4. McEvoy GK, editor. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 1049-1050.
5. Vanessa Bernstein MD. Personal communication. BC Cancer Agency Breast Tumour Group; 25 February 2008.
6. MARTINDALE - The Complete Drug Reference (database on the Internet). Fulvestrant. Thomson MICROMEDEX®, 2008. Available at: http://www.micromedex.com/. Accessed 3 January 2008.
7. BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September 2006.
8. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.