[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].
Administer sub-Q as an implant; insert implant in inner aspect of upper arm. Consult manufacturer’s labeling for proper methods of inserting and removing implants.
Dosage
Available as histrelinacetate; dosage expressed in terms of the salt.
Adults
Prostate Cancer
Sub-Q
One 50-mg implant every 12 months.
Remove implant 12 months after insertion. At time of implant removal, may insert another implant to continue therapy. In limited clinical studies, treatment remains effective for up to 2 years.
Prescribing Limits
Adults
Prostate Cancer
Sub-Q
Use of 2 or 4 implants provides no additional benefit beyond that produced by a single implant.
Special Populations
Renal Impairment
No dosage adjustment required. (See Special Populations under Pharmacokinetics.)
Cautions
Contraindications
Women or pediatric patients. May cause fetal harm when administered to a pregnant woman.
Known hypersensitivity to histrelin or any ingredient in the formulation, other GnRH agonists, or GnRH.
Warnings/Precautions
Warnings
Endocrine Effects
Possible transient increase in serum testosterone concentrations during first week of treatment. Worsening of signs and/or symptoms of prostate cancer and/or development of new manifestations (e.g., bone pain, neuropathy, hematuria, ureteral or bladder outlet obstruction) may occur during first few weeks of therapy.
Ureteral obstruction and spinal cord compression (which may contribute to paralysis with or without fatal complications) reported with GnRH agonists. Observe patients with metastatic vertebral lesions and/or urinary tract obstruction closely during first few weeks of therapy. If spinal cord compression or renal impairment develops, institute standard treatment.
No acute increase in serum testosterone concentration observed following removal of first implant (after 1 year of therapy) and insertion of second implant.
Renal impairment reported. Some patients had a single occurrence of mild impairment (Clcr of 30–59 mL/minute) that returned to normal by the next visit.
General Precautions
Laboratory Monitoring
To monitor response, measure serum concentrations of testosterone and PSA periodically.
Implant Complications
Implant insertion or removal is a surgical procedure. Carefully follow recommended procedures for insertion and removal of implant to minimize potential for complications or for implant expulsion.
Implants are not radio-opaque and, therefore, will not be visible on radiographs. If implant is difficult to locate by palpation, may use ultrasound and computed tomography (CT) scan.
Decrease in Bone Mineral Density
Decrease in bone mineral density possible following long-term therapy with GnRH antagonists and agonists.
Specific Populations
Pregnancy
Category X. (See Contraindications under Cautions.)
Lactation
Contraindicated in women. (See Contraindications under Cautions.)
Pediatric Use
Contraindicated in pediatric patients. (See Contraindications under Cautions.)
Geriatric Use
Studies conducted principally in patients ≥65 years of age, since prostate cancer occurs mainly in an older patient population.
Common Adverse Effects
Local or insertion site reactions (e.g., bruising, pain/soreness/tenderness, erythema), hot flushes (flashes), testicular atrophy, gynecomastia, erectile dysfunction, decreased libido, fatigue, renal impairment, constipation, headache, insomnia, weight loss.
Interactions
No formal drug interaction studies to date.
Pharmacokinetics
Absorption
Bioavailability
Following sub-Q insertion, peak serum concentrations occurred at a median of 12 hours.
Drug is delivered continuously at rate of 50–60 mcg daily over 12 months.
Special Populations
Serum histrelin concentrations are 50% higher in patients with mild to severe renal impairment (Clcr of 15–60 mL/minute). However, increased exposure not considered clinically relevant; dosage adjustment not required.
Distribution
Plasma Protein Binding
Approximately 70%.
Elimination
Elimination Route
No excretion studies to date.
Half-life
Approximately 3.92 hours following sub-Q injection of a 500-mcg dose.
Stability
Storage
Sub-Q
Implant
2–8°C in unopened glass vial, overwrapped in amber plastic pouch and carton. Do not freeze. Protect from light.
Actions
Antineoplastic agent; a synthetic nonapeptide analog of GnRH (LHRH, gonadorelin).
Causes a transient surge in circulating concentrations of LH, FSH, and gonadal steroids (testosterone and dihydrotestosterone in males) following initial administration. Following long-term and continuous administration (generally, 2–4 weeks after initiation of therapy), secretion of LH and FSH is decreased, resulting in marked reduction in serum testosterone concentrations.
Reductions in serum testosterone concentrations following histrelin therapy comparable to those achieved after surgical castration (i.e., <50 ng/dL).
Commercially available as nonbiodegradable, diffusion-controlled implant.
Not active when given orally.
Advice to Patients
Importance of reading and understanding the manufacturer’s patient information leaflet.
Importance of protecting the arm in which the implant was inserted from moisture for 24 hours and refraining from heavy lifting or strenuous exertion with that arm for 7 days after implant insertion.
Importance of understanding required monitoring procedures.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
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.
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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