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Special Alerts
GnRH Agonists: Prescribing Information to Include Increased Risk of Diabetes and Cardiovascular Disease
October 2010
In October 2010, the U.S. Food and Drug Administration (FDA) announced that manufacturers of gonadotropin-releasing hormone (GnRH) agonists will be required to update their prescribing information to include the increased risk of diabetes and cardiovascular disease in men receiving these agents for prostate cancer treatment. In May 2010, the FDA issued a notice regarding initiation of a safety review of GnRH agonists (eg, goserelin, leuprolide) for the treatment of prostate cancer and a possible increased risk of diabetes and cardiovascular disease (ie, heart attack, sudden cardiac death, or stroke). The FDA evaluated preliminary data from one randomized, controlled clinical trial and several observational studies. A Science Advisory statement from the American Heart Association, the American Cancer Society, and the American Urological Association was also considered in the evaluation. Some of these studies demonstrated a small, but statistically significant increased risk of diabetes and/or cardiovascular disease in men receiving GnRH agonist therapy versus men receiving alternative therapy for prostate cancer. The decision to update current labeling was based on the Agency's review of these data.
The FDA believes that although the risk for diabetes and cardiovascular disease appears to be low, patients should be evaluated for these risks. Healthcare providers are also encouraged to:
- Follow prescribing recommendations for GnRH agonists
- Carefully weigh known benefits/risks of GnRH agonists when determining appropriate treatment for prostate cancer
- Monitor patients receiving GnRH-agonist therapy for diabetes (periodic blood glucose and/or glycosylated hemoglobin) and signs/symptoms of cardiovascular disease
- Manage cardiovascular risk factors (blood pressure, weight, cholesterol, blood sugar, smoking) according to current clinical practice
Although GnRH agonists may be used in women and children, there are no known comparable studies evaluating this same risk in either of these populations.
Further information may be found at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230334.htm
Pronunciation
(naf a REL in)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of endometriosis, including pain and reduction of lesions; treatment of central precocious puberty (CPP; gonadotropin-dependent precocious puberty) in children of both sexes
Pregnancy Risk Factor
X
Pregnancy Considerations
Major fetal abnormalities have been reported in some animal studies; a dose-related increase in fetal mortality and decrease in fetal weight was also observed. Ovulation is inhibited and menstruation is stopped when used appropriately for the treatment of endometriosis, however contraception is not assured. Nonhormonal contraception is recommended. Pregnancy should be excluded prior to initiating treatment. There is no evidence that pregnancy rates are enhanced or adversely affected by use.
Lactation
Excretion in breast milk unknown/contraindicated
Contraindications
Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH-agonist analogs, or any component of the formulation; undiagnosed abnormal vaginal bleeding; pregnancy; breast-feeding
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Ovarian cysts: May occur within the first 2 months of therapy and may occur more commonly in women with polycystic ovarian disease.
Disease-related concerns:
• CPP use: When used for the treatment of CPP, some signs of puberty (eg vaginal bleeding, breast enlargement) may occur but should resolve within the first 2 months of therapy.
• Decreased bone mineral density: Use with caution in patients with risk factors for decreased bone mineral density; may pose an additional risk.
Adverse Reactions
Note: Adverse events may be more frequent in the first 6 weeks of treatment due to stimulation of the pituitary-gonadal axis. Sensitivity reactions included chest pain, pruritus, shortness of breath, rash.
CPP: 1% to 10%:
Central nervous system: Emotional lability (6%)
Dermatologic: Acne (10%), seborrhea (3%)
Endocrine & metabolic: Breast enlargement (8%; transient), vaginal bleeding (8%), hot flashes (3%; transient), vaginal discharge (3%)
Respiratory: Rhinitis (5%)
Miscellaneous: Pubic hair increased (5%; transient), body odor (4%), sensitivity reactions (3%)
Endometriosis:
>10%:
Central nervous system: Headache, emotional lability
Dermatologic: Acne
Endocrine & metabolic: Hot flashes (90%), hyperphosphatemia, hypertriglyceridemia, hypocalcemia, libido decreased
Genitourinary: Vaginal dryness
Hematologic: Leukopenia
1% to 10%:
Cardiovascular: Edema
Central nervous system: Depression, insomnia
Dermatologic: Hirsutism, seborrhea
Endocrine & metabolic: Breast size reduced, cholesterol increased, hyperlipidemia, libido increased
Gastrointestinal: Weight gain/loss
Neuromuscular & skeletal: Bone mineral density decreased, myalgia
Respiratory: Nasal irritation
<1%: Arthralgia, breast engorgement, chloasma, eye pain, lactation, maculopapular rash, palpitation, paresthesia, sensitivity reactions, weakness
Postmarketing and/or case reports (any indication): ALT increased, AST increased, pituitary apoplexy, pituitary gland changes
Drug Interactions
Antidiabetic Agents: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Storage
Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
Potent synthetic decapeptide analogue of gonadotropin-releasing hormone (GnRH; LHRH) which is approximately 200 times more potent than GnRH in terms of pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Effects on the pituitary gland and sex hormones are dependent upon its length of administration. After acute administration, an initial stimulation of the release of LH and FSH from the pituitary is observed; an increase in androgens and estrogens subsequently follows. Continued administration of nafarelin, however, suppresses gonadotrope responsiveness to endogenous GnRH resulting in reduced secretion of LH and FSH and, secondarily, decreased ovarian and testicular steroid production.
Pharmacodynamics/Kinetics
Protein binding, plasma: 80%
Metabolism: Degraded by peptidase; forms metabolites
Bioavailability: ~1% to 6%
Half-life elimination: ~3 hours; Metabolites: ~86 hours
Time to peak, serum: 10-45 minutes
Excretion: Urine (44% to 55%, ~3% as unchanged drug); feces (19% to 44%)
Dosage
Intranasal:
Endometriosis: Adults: Female: 1 spray (200 mcg) in 1 nostril each morning and the other nostril each evening starting on days 2-4 of menstrual cycle (total: 2 sprays/day). Dose may be increased to 2 sprays (400 mcg; 1 spray in each nostril) in the morning and evening if amenorrhea is not achieved (total: 4 sprays [800 mcg]/day). Total duration of therapy should not exceed 6 months due to decreases in bone mineral density; retreatment is not recommended by the manufacturer.
Central precocious puberty: Children: Male/Female: 2 sprays (400 mcg) into each nostril in the morning and 2 sprays (400 mcg) into each nostril in the evening (total: 8 sprays [1600 mcg]/day). If inadequate suppression, may increase dose to 3 sprays (600 mcg) into alternating nostrils 3 times/day (total: 9 sprays [1800 mcg]/day).
Administration: Inhalation
Nasal spray: Do not use topical nasal decongestant for at least 2 hours after nafarelin use. Allow ~30 seconds to elapse between sprays. Sneezing during or immediately after dosing should be avoided (may decrease drug absorption).
Monitoring Parameters
CPP: Bone mineral density, GnRH testing (blood LH and FSH levels), measurement of bone age, Tanner staging
Endometriosis: Menstruation, vaginal bleeding or spotting which persists after 2 months of treatment
Test Interactions
Diagnostic tests of pituitary gonadotropic and gonadal functions during and up to 4-8 weeks after discontinuing treatment may be misleading.
Patient Education
Endometriosis: You will begin this treatment between days 2-4 of your regular menstrual cycle. Use daily at the same time (arising and bedtime) and rotate nostrils. Maintain regular follow-up schedule. May cause hot flashes, flushing, or redness; decreased or increased libido; emotional lability; weight gain; decreased breast size; or hirsutism. Report any breakthrough bleeding or continuing menstruation or musculoskeletal pain. Do not use a nasal decongestant within 2 hours after nafarelin.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Emotional lability is common; may cause insomnia
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
For treatment of precocious puberty. Teach patient or caregiver correct timing and administration of nasal spray.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, intranasal [spray]:
Synarel®: 2 mg/mL (8 mL) [contains benzalkonium chloride; 200 mcg/spray; 60 metered sprays]
Pricing: U.S. (www.drugstore.com)
Solution (Synarel)
2 mg/mL (8): $995.63
References
Hornstein MD, Yuzpe AA, Burry K, et al, “Retreatment With Nafarelin for Recurrent Endometriosis Symptoms: Efficacy, Safety and Bone Mineral Density,” Fertil Steril, 1997, 67(6):1013-8.
Tahara M, Matsuoka T, Yokoi T, et al, “Treatment of Endometriosis With a Decreasing Dosage of a Gonadotropin-Releasing Hormone Agonist (Nafarelin): A Pilot Study With Low-Dose Agonist Therapy (“Draw-Back” Therapy),” Fertil Steril, 2000, 73(4):799-804.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2011
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