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Special Alerts
GnRH Agonists: Canadian Labeling Updated to Include Increased Risk of Cardiovascular Disease in Males
September 2011
Health Canada has issued notice to Canadian healthcare professionals and patients that the product labeling for Gonadotropin-Releasing Hormone (GnRH) agonists (eg, goserelin, leuprolide, buserelin, triptorelin, histrelin) has been updated with warnings regarding possible increased risks for cardiovascular events (eg, MI, stroke) in males receiving GnRH agonist therapy for prostate cancer. Although the risk for adverse events appears to be low, healthcare providers are advised to weigh known benefits/risks of GnRH agonists and patient risk factors prior to initiating therapy and to carefully monitor for signs/symptoms of cardiovascular disease during therapy. Patients should be advised to continue with therapy until discussing treatment options with their healthcare provider.
The U.S. prescribing information for these agents has been previously updated with this information.
Further information may be found at
U.S.: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230334.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_122-eng.php
Pronunciation
(GOE se rel in)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of locally confined prostate cancer; palliative treatment of advanced prostate cancer; palliative treatment of advanced breast cancer in pre- and perimenopausal women; treatment of endometriosis, including pain relief and reduction of endometriotic lesions; endometrial thinning agent as part of treatment for dysfunctional uterine bleeding
Pregnancy Risk Factor
X (endometriosis, endometrial thinning); D (advanced breast cancer)
Pregnancy Considerations
Goserelin has been found to be teratogenic and increases pregnancy loss in animal studies. Goserelin induces hormonal changes which increase the risk for fetal loss and use is contraindicated in pregnancy unless being used for palliative treatment of advanced breast cancer. Breast cancer: If used for the palliative treatment of breast cancer during pregnancy, the potential for increased fetal loss should be discussed with the patient.Endometriosis, endometrial thinning: Women of childbearing potential should not receive therapy until pregnancy has been excluded. Nonhormonal contraception is recommended for premenopausal women during therapy and for 12 weeks after therapy is discontinued. Although ovulation is usually inhibited and menstruation may stop, pregnancy prevention is not ensured during goserelin therapy. Changes in reproductive function may occur following chronic administration.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Goserelin is inactivated when used orally. Breast-feeding is not recommended by the manufacturer.
Contraindications
Hypersensitivity to goserelin, GnRH, GnRH agonist analogues, or any component of the formulation; pregnancy (except if using for palliative treatment of advanced breast cancer)
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Cervical resistance: Cervical resistance may be increased; use caution when dilating the cervix.
• Decreased bone density: Has been reported in women and may be irreversible; use caution if other risk factors are present; evaluate and institute preventative treatment if necessary.
• Hypercalcemia: Has been reported in prostate and breast cancer patients with bone metastases.
• Hyperglycemia: Hyperglycemia has been reported in males and may manifest as diabetes or worsening of pre-existing diabetes.
• Hypersensitivity reactions: Allergic hypersensitivity reactions (including anaphylaxis) and antibody formation may occur; monitor.
• Pituitary apoplexy: Rare cases of pituitary apoplexy (frequently secondary to pituitary adenoma) have been observed with GnRH administration (onset from 1 hour to usually <2 weeks); may present as sudden headache, vomiting, visual or mental status changes, and infrequently cardiovascular collapse; immediate medical attention required.
• Spinal cord compression: Has been reported when used for prostate cancer; closely observe patients for weakness and paresthesias in first few weeks of therapy.
• Tumor flare: Transient increases in serum testosterone (in men with prostate cancer) and estrogen (in women with breast cancer) may result in a worsening of disease signs and symptoms (tumor flare) during the first few weeks of treatment.
• Urinary tract obstruction: Has been reported when used for prostate cancer; closely observe patients for urinary tract obstruction in first few weeks of therapy.
Disease-related concerns:
• Cardiovascular disease: Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine, 2010).
Special populations:
• Obese patients: A decreased AUC may be observed when using the 3-month implant in obese patients. Monitor testosterone levels if desired clinical response is not observed.
• Pediatrics: Safety and efficacy have not been established in children.
• Women: Women of childbearing potential should not receive therapy until pregnancy has been excluded. Nonhormonal contraception is recommended during therapy and for 12 weeks after therapy is discontinued. The 3-month implant currently has no approved indications for use in women
Adverse Reactions
Percentages reported with the 1-month implant:
>10%:
Cardiovascular: Peripheral edema (female 21%)
Central nervous system: Headache (female 32% to 75%; male 1% to 5%), emotional lability (female 60%), depression (female 54%; male 1% to 5%), pain (female 17%; male 8%), insomnia (female 11%; male 5%)
Dermatologic: Acne (female 42%), seborrhea (female 26%)
Endocrine & metabolic: Hot flashes (female 57% to 96%; male 62%), libido decreased (female 48% to 61%), sexual dysfunction (male 21%), breast atrophy (female 33%), breast enlargement (female 18%), erections decreased (18%), libido increased (female 12%)
Gastrointestinal: Nausea (female 8% to 11%; male 5%), abdominal pain (female 7% to 11%)
Genitourinary: Vaginitis (75%), pelvic symptoms (female 9% to 18%), dyspareunia (female 14%), lower urinary symptoms (male 13%)
Neuromuscular & skeletal: Bone mineral density decreased (female 23%; ~4% decrease from baseline in 6 months; postmarketing reports in males), weakness (female 11%)
Miscellaneous: Diaphoresis (female 16% to 45%; male 6%), tumor flare (female: 23%), infection (female 13%)
1% to 10%:
Cardiovascular: Arrhythmia, cerebrovascular accident, chest pain, edema, heart failure, hypertension, MI, palpitation, peripheral vascular disorder, tachycardia
Central nervous system: Abnormal thinking, anxiety, chills, dizziness, fever, lethargy, malaise, migraine, nervousness, somnolence
Dermatologic: Alopecia, bruising, dry skin, hair disorder, hirsutism, pruritus, rash, skin discoloration
Endocrine & metabolic: Breast pain, breast swelling/tenderness, dysmenorrhea, gout, hyperglycemia
Gastrointestinal: Anorexia, appetite increased, constipation, diarrhea, dyspepsia, flatulence, ulcer, vomiting, weight gain/loss, xerostomia
Genitourinary: Urinary frequency, urinary obstruction, urinary tract infection, vaginal hemorrhage, vulvovaginitis
Hematologic: Anemia, hemorrhage
Local: Application site reaction
Neuromuscular & skeletal: Arthralgia, back pain , hypertonia, joint disorder, leg cramps, myalgia, paresthesia
Ocular: Amblyopia, dry eyes
Renal: Renal insufficiency
Respiratory: Bronchitis, COPD, cough, epistaxis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection
Miscellaneous: Allergic reaction, flu-like syndrome, voice alteration
<1%, postmarketing, and/or case reports (with monthly or 3-month implant): ALT increased, anaphylaxis, AST increased, diabetes, glucose tolerance decreased, hypercalcemia, hypercholesterolemia, hyperlipidemia, hypersensitivity reactions, hypotension, ovarian cyst, pituitary apoplexy, psychotic disorders, urticaria
Metabolism/Transport Effects
None known.
Drug Interactions
Antidiabetic Agents: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Storage
Zoladex® should be stored at room temperature not to exceed 25°C (77°F). Protect from light.
Mechanism of Action
Goserelin (a gonadotropin-releasing hormone [GnRH] analog) causes an initial increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH), chronic administration of goserelin results in a sustained suppression of pituitary gonadotropins. Serum testosterone falls to levels comparable to surgical castration. The exact mechanism of this effect is unknown, but may be related to changes in the control of LH or down-regulation of LH receptors.
Pharmacodynamics/Kinetics
Onset:
Females: Estradiol suppression reaches postmenopausal levels within 3 weeks and FSH and LH are suppressed to follicular phase levels within 4 weeks of initiation
Males: Testosterone suppression reaches castrate levels within 2-4 weeks after initiation
Duration:
Females: Estradiol, LH and FSH generally return to baseline levels within 12 weeks following the last monthly implant.
Males: Testosterone levels maintained at castrate levels throughout the duration of therapy.
Absorption: SubQ: Rapid and can be detected in serum in 30-60 minutes; 3.6 mg: released slowly in first 8 days, then rapid and continuous release for 28 days
Distribution: Vd: Male: 44.1 L; Female: 20.3 L
Protein binding: 27%
Time to peak, serum: SubQ: Male: 12-15 days, Female: 8-22 days
Half-life elimination: SubQ: Male: ~4 hours, Female: ~2 hours; Renal impairment: Male: 12 hours
Excretion: Urine (>90%; 20% as unchanged drug)
Dosage
SubQ: Adults:
Prostate cancer, advanced:
28-day implant: 3.6 mg every 28 days
12-week implant: 10.8 mg every 12 weeks
Prostate cancer, locally confined (in combination with an antiandrogen and radiotherapy; begin 8 weeks prior to radiotherapy):
Combination 28-day/12-week implant: 3.6 mg implant, followed in 28 days by 10.8 mg implant
28-day implant (alternate dosing): 3.6 mg; repeated every 28 days for a total of 4 doses
Breast cancer, advanced: 3.6 mg every 28 days
Endometriosis: 3.6 mg every 28 days for 6 months
Endometrial thinning: 3.6 mg every 28 days for 1 or 2 doses
Dosing adjustment in renal impairment: No adjustment is necessary
Dosing adjustment in hepatic impairment: No adjustment is necessary
Dosage: Combination Regimens
Prostate cancer:
Bicalutamide-Goserelin
FZ
Administration: Other
SubQ: Administer implant by inserting needle at a 30-45 degree angle into the anterior abdominal wall below the navel line. Goserelin is an implant; therefore, do not attempt to eliminate air bubbles prior to injection (may displace implant). Do not attempt to aspirate prior to injection; if a large vessel is penetrated, blood will be visualized in the syringe chamber (if vessel is penetrated, withdraw needle and inject elsewhere with a new syringe). Do not penetrate into muscle or peritoneum. Implant may be detected by ultrasound if removal is required.
Monitoring Parameters
Bone mineral density, serum calcium, cholesterol/lipids
Prostate cancer: Weakness, paresthesias, and urinary tract obstruction in first few weeks of therapy; screen for diabetes
Test Interactions
Interferes with pituitary gonadotropic and gonadal function tests during and for up to 12 weeks after discontinued
Patient Education
This drug must be implanted under the skin of your abdomen every 28 days or every 3 months; it is important to maintain appointment schedule. If you have diabetes, monitor blood sugar frequently; can cause loss of glycemic control/hyperglycemia. Males or females, you may experience systemic hot flashes; headache; depression; mood swings; insomnia; acne; increased sweating, especially in women; constipation; sexual dysfunction (decreased libido, decreased erection for males, vaginal dryness for females); or bone pain. Symptoms may worsen temporarily during first weeks of therapy. Report chest pain, palpitations, or respiratory difficulty; swelling of extremities; unusual persistent nausea, vomiting, or constipation; infections; unresolved dizziness; skin rash; or paresthesias or muscle weakness.
Geriatric Considerations
No dosage adjustments are needed in the elderly. Monitoring for bone density changes, serum lipid, hemoglobin A1c, blood pressure, and serum calcium changes is recommended.
Additional Information
If removal is necessary, implant may be located by ultrasound.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste disturbances.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Depression, insomnia, and emotional lability are common; may cause anxiety, dizziness, lethargy, malaise, and somnolence; reports of psychosis (rare)
Mental Health: Effects on Psychiatric Treatment
Sexual dysfunction is common; concurrent use with SSRIs or SNRIs may produce additive dysfunction. Response to psychotropic agents may be altered given the effects on mental status.
Nursing: Physical Assessment/Monitoring
Monitor patients for development of diabetes; manage cardiovascular risk factors.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Implant, subcutaneous:
Zoladex®: 3.6 mg (1s) [1 month implant]
Zoladex®: 10.8 mg (1s) [3 month implant]
Pricing: U.S. (www.drugstore.com)
Implant (Zoladex)
10.8 mg (1): $1340.04
References
Ahmann FR, Citrin DL, deHaan HA, et al, “Zoladex: A Sustained-Release, Monthly Luteinizing Hormone-Releasing Hormone Analog for the Treatment of Advanced Prostate Cancer,” J Clin Oncol, 1987, 5(6):912-7.
Baum M, Hackshaw A, Houghton J, et al, “Adjuvant Goserelin in Pre-Menopausal Patients With Early Breast Cancer: Results From the ZIPP Study,” Eur J Cancer, 2006, 42(7):895-904.
Brogden RN and Faulds D, “Goserelin. A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in Prostate Cancer,” Drugs Aging, 1995, 6(4);324-43.
Gnant M, Mlineritsch B, Stoeger H, et al, “Mature Results From ABCSG-12: Adjuvant Ovarian Suppression Combined With Tamoxifen or Anastrozole, Alone or in Combination With Zoledronic Acid, in Premenopausal Women With Endocrine-Responsive Early Breast Cancer,” J Clin Oncol, 2008, 28(15s):533 [abstract 533 from 2008 ASCO Annual Meeting].
Goldspiel BR and Kohler DR, “Goserelin Acetate Implant: A Depot Luteinizing Hormone-Releasing Hormone Analog for Advanced Prostate Cancer,” DICP, 1991, 25(7-8):796-804.
Hackshaw A, Baum M, Fornander T, et al, “Long-Term Effectiveness of Adjuvant Goserelin in Premenopausal Women With Early Breast Cancer,” J Natl Cancer Inst, 2009, 101(5):341-9.
Horwitz EM, Bae K, Hanks GE, et al, “Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer,” J Clin Oncol, 2008, 26(15):2497-504.
Levine GN, D'Amico AV, Berger P, et al, “Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk. A Science Advisory from the American Heart Association, American Cancer Society, and American Urological Association,” Circulation, 2010, 121(6):833-40
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Prostate Cancer,” Version 3.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf
Roach M 3rd, Bae K, Speight J, et al, “Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610,” J Clin Oncol, 2008, 26(4):585-91.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
Content last modified January 2012
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