ATC Class: H01CA02
VA Class: HS900
Chemical Name: 6-[3-(2-naphthalenyl)-d-alanine]-hydrate acetate (salt) luteinizing hormone-releasing factor (pig)
Molecular Formula: C66H83N17O13•xC2H4O2•yH2O
CAS Number: 86220-42-0
Gonadotropin-releasing hormone (GnRH) agonist; synthetic decapeptide analog of GnRH (luteinizing hormone-releasing hormone, gonadorelin); structurally related to goserelin, leuprolide, and triptorelin.
Uses for Nafarelin
Palliative treatment of endometriosis (e.g., pain relief, reduction in endometrial lesions). Experience limited to women ≥18 years of age treated for 6 consecutive months.
Treatment of central (via activation of the hypothalamic-pituitary-gonadal axis) precocious puberty (true precocious puberty, GnRH-dependent precocious precocity, complete isosexual precocity) in children of both sexes (designated as an orphan drug by FDA for this use).
Nafarelin Dosage and Administration
Delay administration of topical decongestants for ≥2 hours after nafarelin administration.
Exclude pregnancy prior to initiating therapy.
Initiate treatment between days 2–4 of the menstrual cycle.
Ovulation may not be suppressed at recommended dosage; use of an effective nonhormonal method of contraception is essential.
If menstrual bleeding continues after first 2 months, consider lack of compliance. If compliance problems excluded, may increase dosage. (See Dosage: Endometriosis under Dosage and Administration.)
- Precocious Puberty
Evaluate bone age and growth velocity within 3–6 months of nafarelin initiation and periodically thereafter.
If lack of suppression of the pituitary-gonadal axis, consider noncompliance with the treatment regimen. Recommend dosing be done by caregivers. If compliance problems excluded, reconsider possibility of gonadotropin-independent sexual precocity. If both are excluded, may increase dosage. (See Dosage: Precocious Puberty under Dosage and Administration.)
Administer by nasal inhalation using a metered spray pump.
Avoid sneezing during or immediately after administration.
Prior to initial use, prime the nasal inhaler. To prime, hold bottle upright and quickly depress the side arms of pump toward the bottle 7–10 times, until a fine spray occurs.
Clear nasal passages prior to administration.
Tilt the head slightly backward, insert the spray tip into one nostril, and point the tip toward the back of the nose. Rapidly and firmly press and actuate into the nostril while holding the other nostril closed and concurrently inspire through the nose. After removing the spray tip from the nostril, remain with head tilted backward for a few seconds. If additional sprays are indicated for the same nostril, wait 30 seconds before repeating the procedure.
Following administration, rinse spray tip with warm water while wiping tip with finger or soft cloth for 15 seconds; dry spray tip with a soft cloth or tissue.
Available as nafarelin acetate; dosage is expressed in terms of nafarelin.
After priming, the commercially available nasal pump delivers 200 mcg of nafarelin per spray and approximately 60 sprays per 8-mL container.
Missed doses may cause breakthrough bleeding or ovulation, or restart pubertal development. Full efficacy is dependent on dosage compliance for full duration of treatment.
Children: 2 sprays in each nostril (800 mcg total) in the morning and 2 sprays in each nostril in the evening (total daily dosage: 1600 mcg).
If lack of suppression of the pituitary-gonadal axis, may increase dosage to 3 sprays (600 mcg) into alternating nostrils 3 times daily (total daily dosage: 1800 mcg).
Continue therapy until resumption of puberty is desired.
Women ≥18 years of age: 1 spray (200 mcg) in one nostril every morning and 1 spray (200 mcg) in the other nostril every evening (total daily dosage: 400 mcg) for 6 consecutive months.
If regular menstruation persists after 2 months of therapy, may increase dosage to 1 spray in each nostril (400 mcg total) in the morning and 1 spray in each nostril in the evening (total daily dosage: 800 mcg).
Retreatment with additional courses of therapy not recommended currently by manufacturer. (See Retreatment in Endometriosis under Cautions.)
No special population dosage recommendations at this time.
Cautions for Nafarelin
Known hypersensitivity to GnRH, nafarelin, other GnRH agonist analogs, or any ingredient in the formulation.
Known or suspected pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Abnormal vaginal bleeding of unknown etiology.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals. (See Contraindications under Cautions.)
Exclude pregnancy immediately prior to initiation of therapy. Use nonhormonal method of contraception during therapy. If used during pregnancy or if patient becomes pregnant during therapy, discontinue drug and apprise of potential fetal hazard.
Although nafarelin usually inhibits ovulation and stops menstruation, contraception is not ensured, especially if patient misses successive doses.
Patient Monitoring in Central Precocious Puberty
Carefully exclude other causes of sexual precocity (e.g., congenital adrenal hyperplasia, testotoxicosis, testicular tumors, other autonomous feminizing or masculinizing disorder) and establish diagnosis of central precocious puberty before initiating treatment.
Regularly monitor patients, especially during the initial 6–8 weeks of therapy, to ensure compliance and adequate patient response (i.e., rapid suppression of pituitary-gonadal function). (See General under Dosage and Administration and also see Dosage: Precocious Puberty under Dosage and Administration.)
Assess bone age and growth velocity within 3–6 months of initiation of therapy and periodically thereafter.
Possible sensitivity reactions (e.g., shortness of breath, chest pain, urticaria, rash, pruritus) reported.
Pituitary apoplexy, a clinical syndrome secondary to pituitary gland infarction (e.g., headache, vomiting, visual changes, ophthalmoplegia, altered mental status, possible cardiovascular collapse) reported rarely following GnRH agonist administration. Most cases occurred within 2 weeks of first dose, although they have occurred within the first hour in some patients. Immediate medical attention required.
Endocrine Effects in Endometriosis
Ovarian cysts reported during the first 2 months of therapy in adult women; most cases occurred in patients with polycystic ovarian disease. May resolve spontaneously (usually within 4–6 weeks of therapy); may require discontinuance of the drug and/or surgical intervention. Relevance to females <18 years of age unknown.
Decreases in vertebral trabecular bone mineral density and total vertebral bone mass reported in women; some loss may not be reversible. Concurrent use of hormone replacement therapy or bisphosphonates (e.g., alendronate) may minimize bone mineral loss associated with therapy without compromising efficacy of endometriosis management.
If major risk factors for decreased bone mineral content (e.g., chronic alcohol and/or tobacco use, strong family history of osteoporosis, chronic use of drugs that can reduce bone mass [e.g., anticonvulsants, corticosteroids]), weigh risks and benefits carefully before initiating therapy. (See Retreatment in Endometriosis under Cautions.)
Possible increased risk of diabetes in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of diabetes in women and children receiving GnRH agonists not performed to date.
Retreatment in Endometriosis
Safety established only for initial 6-month treatment course; therefore, manufacturer cannot recommend retreatment. (See Endocrine Effects in Endometriosis under Cautions.)
If considering retreatment after initial 6-month course, assess bone density to ensure values are within normal limits before beginning retreatment. Repeated courses not advised in patients with major risk factors for loss of bone mineral content.
May alter serum lipoprotein concentrations; risk of increased triglycerides and total cholesterol.
Hyperphosphatemia and eosinophilia may occur.
Hypocalcemia and leukopenia may occur.
Thromboembolic events (e.g., DVT, PE, MI, stroke, TIA) reported. Possible increased risk of cardiovascular disease (e.g., MI, sudden cardiac death, stroke) in patients receiving GnRH agonists for treatment of prostate cancer. Studies evaluating risk of cardiovascular disease in women and children receiving GnRH agonists not performed to date.
Category X. (See Contraindications and also Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether nafarelin is distributed into milk. Do not use in nursing women. (See Contraindications under Cautions.)
Safety and efficacy not established in children <18 years of age for uses other than treatment of central precocious puberty.
Common Adverse Effects
Women with endometriosis: Hot flushes (flashes), decreased libido, vaginal dryness, headache, emotional lability, acne, myalgia, reduction in breast size, nasal irritation.
Children with central precocious puberty: Acne, transient breast enlargement, emotional lability, transient increases in pubic hair, body odor, seborrhea, hot flushes (flashes), rhinitis, vaginal bleeding, white or brown vaginal discharge.
Interactions for Nafarelin
No formal drug interaction studies to date.
The manufacturer states drug interactions not expected to occur because nafarelin is a peptide mainly degraded by peptidases and not by CYP microsomal enzymes and because of the drug’s limited protein binding.
Specific Drugs and Laboratory Tests
Drug or Test
Decongestants (topical nasal)
Delay administration of a topical nasal decongestant ≥2 hours after administration of nafarelin
Tests, diagnostic tests of pituitary gonadotropic and gonadal function
Possible erroneous results when diagnostic tests of pituitary gonadotropic and gonadal function obtained during treatment and up to 4–8 weeks after discontinuance of nafarelin
Normal function usually restored 4–8 weeks after discontinuance of nafarelin
Rapidly absorbed into systemic circulation following nasal administration.
Bioavailability averages 2.8% (range 1.2–5.6%) in adult women.
Nasal congestion or rhinitis does not appear to affect bioavailability.
Following intranasal administration in children and adult women, maximum serum concentrations occur at 10–45 minutes and 10–40 minutes, respectively.
Not known whether nafarelin is distributed into milk.
Plasma Protein Binding
About 80% at 4°C.
Excreted in urine (44–55%) and feces (19–44%) mainly as metabolites.
Children: 2.5 hours.
Women: 3 hours.
Upright at 25°C (may be exposed to 15–30°C). Protect from light; do not freeze.
Potent agonistic analog of GnRH; greater activity than naturally occurring GnRH.
Initially produces a transient surge in circulating levels of estradiol, testosterone, LH, and FSH.
Following chronic and continuous administration (generally 4 weeks after therapy initiation), causes a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis.
In children receiving continuous administration of adequate doses, serum LH, testosterone, and estradiol concentrations return to prepubertal levels, resulting in suppression of secondary sexual characteristics and decreased rate of linear growth and skeletal maturation. Initial estrogen withdrawal bleeding may occur, generally ≤6 weeks after therapy initiation; menstruation should cease thereafter. Effects are usually reversible following therapy cessation.
In adult women, serum estradiol, FSH, and LH concentrations usually return to pretreatment levels following discontinuance of therapy.
Advice to Patients
Importance of providing patient a copy of manufacturer’s patient information.
Importance of full compliance with nafarelin dosing for efficacy. If clinician increases the daily dosage, importance of having an adequate supply for uninterrupted treatment.
Importance of not sneezing during or immediately after administering nafarelin nasal solution.
Inform patients to consult clinician in case of rhinitis. If a topical nasal decongestant is needed, administer the decongestant at least 2 hours after nafarelin.
Risk of sensitivity reaction. Risk of other adverse effects, including decreased bone mineral density in women.
Importance of promptly reporting sudden onset of headache, vomiting, or visual changes to clinician.
Advise women of childbearing potential to use an effective nonhormonal contraceptive method (e.g., diaphragm with contraceptive jelly, IUD, condoms) instead of a hormonal method during nafarelin therapy.
Advise women to avoid pregnancy and not to breast-feed during therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. Importance of informing clinicians of chronic alcohol and/or tobacco use.
Importance of informing patients of other important precautionary information. (See Cautions.)
- Central Precocious Puberty
Importance of advising patients with precocious puberty that each nasal solution bottle should be used for ≤7 days unless otherwise directed by a clinician. At the end of 7 days, dispose of bottle and do not reuse.
Inform patients and parents/guardians that the suppressive effects of nafarelin in children are reversible and that initial transient increases in the signs of puberty (e.g., vaginal bleeding, breast enlargement) are possible.
Advise patients and parents/guardians that menstrual flow may occur during first 6 weeks of treatment, even if not menstruating previously; advise that menstrual flow should stop after first 6 weeks.
Importance of advising women with endometriosis to administer the first dose between the second and fourth day after the beginning of menstrual bleeding.
Inform the patient that each nasal solution bottle should be used for ≤30 days. At the end of 30 days, a small amount of liquid will be left in the bottle; do not use the remaining amount.
Advise women that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed. Importance of contacting clinician to exclude the possibility of pregnancy if this occurs.
Advise patients that irregular vaginal spotting or bleeding may occur for the first 2 months of therapy; duration and intensity may vary. Importance of informing clinician if regular menstruation persists after 2 months of therapy.
Advise patients to discuss the possibility of osteoporosis with their clinician before starting therapy. Inform patients that repeat treatments increase the risk of bone loss.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
200 mcg (of nafarelin) per metered spray
AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 16, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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