[Posted 10/20/2010] ISSUE: Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.
BACKGROUND: GnRH agonists are approved to treat the symptoms (palliative treatment) of advanced prostate cancer. The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established. FDA’s notification to manufacturers of GnRH agonists to add this safety information is based on the Agency’s review of several published studies. Most of the studies reviewed by FDA reported small but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists.
RECOMMENDATIONS: Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice. For more information visit the FDA website at: [Web] and [Web].
[Posted 05/03/2010] FDA notified healthcare professionals and patients of FDA’s preliminary and ongoing review which suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists, drugs that suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer.
Most of the studies reviewed by FDA reported small, but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists. FDA’s review is ongoing and the agency has not made any conclusions about GnRH agonists and whether they increase the risk of diabetes and cardiovascular disease in patients receiving these medications for prostate cancer.
Healthcare professionals and patients should be aware of these potential safety issues and carefully weigh the benefits and risks of GnRH agonists when determining treatment choices. FDA recommends that patients receiving GnRH agonists should be monitored for development of diabetes and cardiovascular disease. Patients should not stop their treatment with GnRH agonists unless told to do so by their healthcare professional.
Some GnRH agonists are also used in women and in children for other indications than those above. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women and children taking GnRH agonists. For more information visit the FDA website at: [Web] and [Web].
Palliative treatment of advanced prostate cancer. Considered one of several first-line options for hormonal therapy; other options include orchiectomy, estrogens, and antiandrogens.
In clinical studies, goserelin (3.6 mg every 4 weeks) was as effective as orchiectomy. Clinical outcome in patients receiving goserelin 10.8 mg every 12 weeks expected to be similar to that of patients receiving goserelin 3.6 mg every 4 weeks.
Also used as an adjunct to radiation therapy in patients with stage III (C) prostate cancer.
Treatment of locally confined stage T2b-T4 (B2-C) prostate cancer in conjunction with flutamide and radiation therapy.
Endometriosis
Palliative treatment of endometriosis. Experience with goserelin has been limited to women ≥18 years of age who received consecutive therapy (3.6 mg every 4 weeks) for 6 months.
Breast Cancer
Palliative treatment of advanced breast cancer in premenopausal and perimenopausal women.
Dysfunctional Uterine Bleeding
Used as an endometrial-thinning agent prior to endometrial ablation procedures for the treatment of dysfunctional uterine bleeding.
Dosage and Administration
Administration
Sub-Q
Administered as a biodegradable implant into the upper abdominal wall.
Implants containing goserelin 3.6 mg are administered every 4 weeks.
Implants containing goserelin 10.8 mg are administered every 12 weeks.
Adherence to the recommended schedule recommended; a delay of a few days is permitted.
A local anesthetic may be given prior to implantation.
The implant may be located by ultrasound in the event that it needs to be removed.
Consult the manufacturer’s labeling for proper methods of administration and associated precautions.
Dosage
Available as goserelin acetate; dosage expressed in terms of goserelin.
Adults
Prostate Cancer
Advanced Prostate Cancer
Sub-Q
One implant containing 3.6 mg every 4 weeks or one implant containing 10.8 mg every 12 weeks. Intended for long-term administration unless it is clinically inappropriate.
Stage III (C) prostate cancer (as an adjunct to radiation therapy): One implant containing 3.6 mg every 4 weeks; initiate therapy on the first day of radiation or during the last week of radiation.
Stage B2-CProstate Cancer
Sub-Q
One implant containing 3.6 mg every 4 weeks starting 8 weeks prior to radiation therapy and continuing for a total of 4 doses recommended by the manufacturer. Alternatively, one implant containing 3.6 mg implanted 8 weeks prior to radiation therapy and followed by one implant containing 10.8 mg on day 28 (4 weeks after initial 3.6-mg dose) recommended by the manufacturer.
Endometriosis
Sub-Q
One implant containing 3.6 mg every 4 weeks for 6 consecutive months. Retreatment with additional courses currently not recommended; safety has only been established for a 6-month course of therapy; there are concerns about potential long-term effects on bone density. Assess bone density if retreatment for recurrence is considered. (See Musculoskeletal Effects under Cautions.)
Breast Cancer
Sub-Q
One implant containing 3.6 mg every 4 weeks. Consider dosage increase to 7.2 mg (3.6 mg implanted to 2 different sites) every 4 weeks in women whose serum estradiol concentrations are not reduced to postmenopausal levels after 8 weeks. Intended for long-term administration unless clinically inappropriate.
Dysfunctional Uterine Bleeding
Sub-Q
One implant containing 3.6 mg 4 weeks before endometrial ablation. Alternatively, the initial 3.6-mg dose of goserelin can be followed by a second 3.6-mg dose 4 weeks after the first dose; surgery should be performed 2–4 weeks after the second dose.
Prescribing Limits
Adults
Endometriosis
Sub-Q
Maximum 3.6 mg every 4 weeks for 6 consecutive months.
Special Populations
No special population dosage recommendations at this time.
Hepatic Impairment
Dosage adjustment not needed.
Renal Impairment
Dosage adjustment not needed. (See Special Populations under Pharmacokinetics.)
Cautions
Contraindications
Known hypersensitivity to goserelin or any ingredient in the formulation, other GnRH agonists, or GnRH.
The implant containing 10.8 mg of goserelin should not be used in women; insufficient data available to determine whether this preparation is associated with reliable suppression of serum estradiol.
Warnings/Precautions
Warnings
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals. Exclude pregnancy before initiating therapy in women. Women of childbearing potential should avoid pregnancy and use an effective nonhormonal method of contraception during therapy and continue contraception until the return of menses or for at least 12 weeks following the last dose of goserelin.
If a patient with endometriosis or undergoing endometrial thinning becomes pregnant during therapy, discontinue the drug and advise patient about potential fetal hazard.
If used during pregnancy (i.e., in women with advanced breast cancer), apprise of potential fetal hazard.
Continuous use of goserelin usually inhibits ovulation and stops menstruation; however, contraception is not ensured.
Endocrine Effects
Transient increases in serum testosterone (in men) or estrogen (in women) concentrations during the initial weeks of therapy may result in worsening (flare) of signs and/or symptoms (e.g., increased bone pain) of prostate or breast cancer and/or development of new manifestations during the initial weeks of therapy. Concomitant therapy with an antiandrogen (e.g., bicalutamide, flutamide, nilutamide) 1 week before and during the first few weeks of goserelin therapy may minimize disease flare in men with prostate cancer.
Cases of spinal cord compression and/or ureteral obstruction reported in men with prostate cancer. If spinal cord compression or renal impairment develops, institute standard treatment of these complications; in extreme cases, consider an immediate orchiectomy. Caution in patients at particular risk of developing spinal cord compression or ureteral obstruction; observe closely during the first month of therapy. Treat spinal cord compression or ureteral obstruction before initiating goserelin.
Hypercalcemia
Hypercalcemia reported in patients with prostate or breast cancer with bone metastases. Initiate appropriate treatment if hypercalcemia develops.
Possible increase in cervical resistance. Perform cervical dilation carefully following use of goserelin as an endometrial thinning agent.
Patient Monitoring
Determine serum testosterone concentrations periodically in patients with prostate cancer in whom the anticipated clinical or biochemical response to goserelin has not been achieved.
Reduction in serum prostate specific antigen (PSA) concentrations may provide information about duration of progression-free status in men with prostate cancer. However, decreases in PSA concentrations may occur independent of tumor response; clinicians cannot rely solely on PSA concentrations to monitor a patient’s response.
Musculoskeletal Effects
Decreases in bone mineral density, osteoporosis, and bone fracture have been reported in men, and decreases in bone mineral density have been reported in women.
For management of endometriosis in women, concurrent use of hormone replacement therapy or bisphosphonates (e.g., alendronate) may minimize bone mineral loss associated with GnRH agonist therapy without compromising efficacy of these drugs.
Risk of bone mineral density loss may be increased in patients with a history of prior therapy that resulted in bone mineral density loss and/or patients with risk factors for decreased bone mineral density (e.g., chronic alcohol abuse, tobacco abuse, family history of osteoporosis, chronic use of anticonvulsants or corticosteroids).
Cardiovascular Effects
Possible transient changes in BP (hypotension or hypertension).
Category D (advanced breast cancer); category X (endometriosis, endometrial-thinning agent) (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing.
Pediatric Use
Safety and efficacy not established.
Geriatric Use
Clinical studies for use in prostate cancer have been conducted principally in patients ≥65 years of age.
Renal Impairment
Incidence of adverse effects not increased in patients with renal impairment receiving goserelin 10.8 mg.
Common Adverse Effects
Men: Hot flushes (flashes), sexual dysfunction, decreased erections, lower urinary tract symptoms, pain (worsened in the first month).
3.6 mg: Peak plasma concentrations achieved within 12–15 days in men and 8–22 days in women.
10.8 mg: Peak plasma concentrations achieved within 24 hours in men.
Duration
3.6 mg: 4 weeks.
10.8 mg: 12 weeks.
Special Populations
Long-term administration of goserelin 10.8 mg in patients with renal impairment not associated with accumulation of goserelin.
Distribution
Plasma Protein Binding
27.3%.
Elimination
Metabolism
Undergoes hydrolysis of the C-terminal amino acids.
Elimination Route
Eliminated predominately in urine (90%) as metabolites and unchanged drug (20%).
Half-life
Men: 4.16–4.2 hours.
Women: 2.3 hours.
Special Populations
Men with Clcr <20 mL/minute: Half-life of 12.1 hours reported.
Stability
Storage
Sub-Q
Implant
Room temperature (<25°C).
Actions
A synthetic decapeptide analog of GnRH; structurally related to leuprolide, nafarelin, and triptorelin.
A potent inhibitor of gonadotropin secretion when given continuously.
Initially, circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol surge transiently. Following chronic and continuous administration (generally, 2–4 weeks after initiation of therapy), produces a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis.
Reductions in serum testosterone concentrations in males receiving goserelin are comparable to those achieved after surgical castration (i.e., <50 ng/dL). Consequently, physiologic functions and tissues dependent on testosterone for maintenance become quiescent.
In most premenopausal women, serum estradiol concentrations are reduced to levels comparable to those observed after menopause within 3 weeks of initiating therapy. Consequently, physiologic functions and tissues dependent on gonadal steroids (estrogen) for maintenance become quiescent.
Advice to Patients
Risk of worsening manifestations of prostate or breast cancer during initial weeks of therapy.
Risk of anaphylactoid and other sensitivity reactions.
Necessity of advising women to avoid pregnancy during therapy and until the return of menses or 12 weeks after administration of the last 3.6-mg dose of goserelin.
Importance of women informing their clinician if regular menstruation persists. Women also should be advised that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Zoladex® (available as prefilled disposable syringe)
AstraZeneca
10.8 mg (of goserelin)
Zoladex® (available as prefilled disposable syringe)
AstraZeneca
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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