Synarel

Generic Name: Nafarelin Acetate
Class: Gonadotropins
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

Special Alerts:

[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: and .

[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: and .

Introduction

Gonadotropin-releasing hormone (GnRH) agonist; synthetic decapeptide analog of GnRH (luteinizing hormone-releasing hormone, gonadorelin); structurally related to goserelin, leuprolide, and triptorelin.^{1 2 3}

Uses for Synarel

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Endometriosis

Palliative treatment of endometriosis (e.g., pain relief, reduction in endometrial lesions).^{2 3 4 5 8 c} Experience limited to women ≥18 years of age treated for 6 consecutive months.²

Precocious Puberty

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^{1 3 6 7 10 12 e} (designated as an orphan drug by FDA for this use).⁷

Synarel Dosage and Administration

General

• 
  

  Delay administration of topical decongestants for ≥2 hours after nafarelin administration.^{1 2 c e}

  
  

• Endometriosis


• 
  

  Exclude pregnancy prior to initiating therapy.²

  
  


• 
  

  Initiate treatment between days 2–4 of the menstrual cycle.^{2 3 c}

  
  


• 
  

  Ovulation may not be suppressed at recommended dosage; use of an effective nonhormonal method of contraception is essential.^{1 2 c}

  
  


• 
  

  If menstrual bleeding continues after first 2 months, consider lack of compliance.^b If compliance problems excluded, may increase dosage.^b (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.^{1 6 12}

  
  


• 
  

  If lack of suppression of the pituitary-gonadal axis, consider noncompliance with the treatment regimen.^d Recommend dosing be done by caretakers.^d If compliance problems excluded, reconsider possibility of gonadotropin-independent sexual precocity.^d If both are excluded, may increase dosage.^d (See Dosage: Precocious Puberty under Dosage and Administration.)

  
  

Administration

Intranasal Inhalation

Administer by nasal inhalation using a metered spray pump.^{1 2 3 c e}

Avoid sneezing during or immediately after administration.^{1 2}

Prior to initial use, prime the nasal inhaler.⁹ To prime, hold bottle upright and quickly depress the side arms of pump toward the bottle 7–10 times, until a fine spray occurs.^{c e}

Clear nasal passages prior to administration.⁹

Tilt the head slightly backward, insert the spray tip into one nostril, and point the tip toward the back of the nose.^{9 12} Rapidly and firmly press and actuate into the nostril while holding the other nostril closed and concurrently inspire through the nose.⁹ After removing the spray tip from the nostril, remain with head tilted backward for a few seconds.⁹ If additional sprays are indicated for the same nostril, wait 30 seconds before repeating the procedure.^{1 9}

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.^{c e}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as nafarelin acetate; dosage is expressed in terms of nafarelin.^{1 2}

After priming, the commercially available nasal pump delivers 200 mcg of nafarelin per spray and approximately 60 sprays per 8-mL container.²

Missed doses may cause breakthrough bleeding, ovulation, or restart pubertal development.^{c e} Full efficacy is dependent on dosage compliance for full duration of treatment.^{c e}

Pediatric Patients

Precocious Puberty

Intranasal

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).^{1 3 c e}

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).¹

Continue therapy until resumption of puberty is desired.^{1 12 e}

Adults

Endometriosis

Intranasal

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.^{2 3 12 c}

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).²

Retreatment with additional courses of therapy not recommended currently by manufacturer.² (See Retreatment in Endometriosis under Cautions.)

Special Populations

No special population dosage recommendations at this time.^{1 2}

Cautions for Synarel

Contraindications

• 
  

  Known hypersensitivity to GnRH, nafarelin, other GnRH agonist analogs, or any ingredient in the formulation.^{1 2 e}

  
  


• 
  

  Known or suspected pregnancy.^{1 2} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  Lactation.^{1 2}

  
  


• 
  

  Abnormal vaginal bleeding of unknown etiology.^{1 2}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals.^{1 2} (See Contraindications under Cautions.)

Exclude pregnancy immediately prior to initiation of therapy.² Use nonhormonal method of contraception during therapy.^{1 2} If used during pregnancy or if patient becomes pregnant during therapy, discontinue drug and apprise of potential fetal hazard.^{1 2}

Although nafarelin usually inhibits ovulation and stops menstruation, contraception is not ensured, especially if patient misses successive doses.^{1 2}

Patient Monitoring in Central Precocious Puberty

Carefully exclude other causes of sexual precocity (e.g., congenital adrenal hyperplasia, testotoxicosis, testicular tumors) and establish diagnosis of central precocious puberty before initiating treatment.^d

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).¹ (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.^{1 6 12}

Sensitivity Reactions

Possible sensitivity reactions (e.g., shortness of breath, chest pain, urticaria, rash, pruritus) reported.^{1 2}

Major Toxicities

Pituitary Apoplexy

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.^{b d} Most cases occurred within 2 weeks of first dose.^{b d} Immediate medical attention required.^{b d}

General Precautions

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.^{1 2} May resolve spontaneously (usually within 4–6 weeks of therapy); may require discontinuance of the drug and/or surgical intervention.^{1 2} Relevance to females <18 years of age unknown.^d

Decreases in vertebral trabecular bone mineral density and total vertebral bone mass reported in women; some loss may not be reversible.² 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.¹¹

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.^b (See Retreatment in Endometriosis under Cautions.)

Retreatment in Endometriosis

Safety established only for initial 6-month treatment course; therefore, manufacturer cannot recommend retreatment.^b (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.^b Repeated courses not advised in patients with major risk factors for loss of bone mineral content.^b

Laboratory Abnormalities

May alter serum lipoprotein concentrations; risk of increased triglycerides and total cholesterol.^b

Hyperphosphatemia and eosinophilia may occur.^b

Hypocalcemia and leukopenia may occur.^b

Specific Populations

Pregnancy

Category X.^{1 2} (See Contraindications and also Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether nafarelin is distributed into milk.^{1 2} Do not use in nursing women.^{1 2} (See Contraindications under Cautions.)

Pediatric Use

Safety and efficacy not established in children <18 years of age for uses other than treatment of central precocious puberty.^{1 2 12}

Common Adverse Effects

Women with endometriosis: Hot flushes (flashes), decreased libido, vaginal dryness, headache, emotional lability, acne, myalgia, reduction in breast size, nasal irritation.^{2 3 4 5 c}

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.^{1 6}

Interactions for Synarel

No formal drug interaction studies to date.^{1 2}

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.^{1 2}

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Decongestants (topical nasal)	Possible interactionb	Delay administration of a topical nasal decongestant ≥2 hours after administration of nafarelin1 2
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 nafarelinb	Normal function usually restored 4–8 weeks after discontinuance of nafarelinb

Synarel Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed into systemic circulation following nasal administration.^{2 d}

Bioavailability averages 2.8% (range 1.2–5.6%) in adult women.^{2 d}

Nasal congestion or rhinitis does not appear to affect bioavailability.^{a b d}

Following intranasal administration in children and adult women, maximum serum concentrations occur at 10–45 minutes and 10–40 minutes, respectively.^{b d}

Distribution

Extent

Not known whether nafarelin is distributed into milk.^{1 2}

Plasma Protein Binding

About 80% at 4°C.^{b d}

Elimination

Elimination Route

Excreted in urine (44–55%) and feces (19–44%) mainly as metabolites.^{b d}

Half-life

Children: 2.5 hours.^d

Women: 3 hours.^{b d}

Stability

Storage

Intranasal

Nasal Solution

Upright at 25°C (may be exposed to 15–30°C).^{b c d e} Protect from light; do not freeze.^{b c d e}

ActionsActions

• 
  

  Potent agonistic analog of GnRH;^{b d} greater activity than naturally occurring GnRH.^{1 2 3}

  
  


• 
  

  Initially produces a transient surge in circulating levels of estradiol, testosterone, LH, and FSH.^{1 2 3}

  
  


• 
  

  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.^{1 2 3}

  
  


• 
  

  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.^{1 6 12} Initial estrogen withdrawal bleeding may occur, generally ≤6 weeks after therapy initiation; menstruation should cease thereafter.^d Effects are usually reversible following therapy cessation.¹

  
  


• 
  

  In adult women, serum estradiol, FSH, and LH concentrations usually return to pretreatment levels following discontinuance of therapy.^{3 4}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of providing patient a copy of manufacturer’s patient information.^{b c d e}

  
  


• 
  

  Importance of full compliance with nafarelin dosing for efficacy.^{1 2 c e} If clinician increases the daily dosage, importance of having an adequate supply for uninterrupted treatment to complete the recommended treatment period.^{c d e}

  
  


• 
  

  Importance of not sneezing during or immediately after administering nafarelin nasal solution.^{1 2 9}

  
  


• 
  

  Inform patients that if a topical nasal decongestant is needed, delay administration of the decongestant 2 hours after nafarelin administration.^{1 2 9}

  
  

• 
  

  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.^{1 2 c}

  
  


• 
  

  Advise women to avoid pregnancy and not to breast-feed during therapy.^{2 c}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, as well as any concomitant illnesses.^{1 2} Importance of informing clinicians of chronic alcohol and/or tobacco use.^{b c}

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Central Precocious Puberty

• 
  

  Each nasal solution bottle should be used for ≤7 days unless otherwise directed by a clinician.^e At the end of 7 days, dispose of bottle and do not reuse.^e

  
  


• 
  

  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.^{1 9}

  
  


• 
  

  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.^e

  
  

Endometriosis

• 
  

  Administer the first dose between the second and fourth day after the beginning of menstrual bleeding.^{b c}

  
  


• 
  

  Inform the patient that each nasal solution bottle should be used for ≤30 days.^c At the end of 30 days, a small amount of liquid will be left in the bottle; do not use the remaining amount.^c

  
  


• 
  

  Advise women that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed.^{9 b c} Importance of contacting clinician to exclude the possibility of pregnancy if this occurs.^c

  
  


• 
  

  Advise patients that irregular vaginal spotting or bleeding may occur for the first 2 months of therapy; duration and intensity may vary.^{b c} Importance of informing clinician if regular menstruation persists after 2 months of therapy.^{2 c}

  
  


• 
  

  Advise patients to discuss the possibility of osteoporosis with their clinician before starting therapy.^{b c} Inform patients that repeat treatments increase the risk of bone loss.^{b c}

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Nafarelin Acetate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Nasal	Solution	200 mcg (of nafarelin) per metered spray	Synarel	Searle

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Synarel 2MG/ML Solution (PFIZER U.S.): 8/$995.63 or 16/$1922.75

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Searle. Synarel (nafarelin acetate) nasal solution 2 mg/mL as nafarelin base) prescribing information for central precocious puberty dated 2000 Jun). In Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:3204-5.

2. Searle. Synarel (nafarelin acetate) nasal solution 2 mg/mL (as nafarelin base) prescribing information for endometriosis (dated 2000 Jun). In Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:3205-6.

3. Chrisp P, Goa KL. Nafarelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. 1990; 39:523-51. [PubMed 2140979]

4. Henzl MR. Gonadotropin-releasing hormone (GnRH) agonists in the management of endometriosis: a review. Clin Obstet Gynecol. 1988; 31:840-56. [PubMed 3067932]

5. Henzl M, Corson SL, Moghissi K et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis: a multicenter double-blind comparative clinical trial. N Engl J Med. 1988; 318:485-9. [IDIS 239227] [PubMed 2963213]

6. Lee PA. Central precocious puberty: an overview of diagnosis, treatment, and outcome. Endocrinol Metab Clin North Am. 1999; 28:901-18. [PubMed 10609126]

7. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; (2002 Feb 3). From FDA web site.

8. Zhao SZ, Kellerman LA, Francisco CA et al. Impact of nafarelin and leuprolide for endometriosis on quality of life and subjective clinical measures. J Reprod Med. 1999; 44:1000-6. [IDIS 441290] [PubMed 10649809]

9. Syntex. Synarel (nafarelin acetate) nasal solution 2 mg/mL (as nafarelin base) information for patients. Palo Alto, CA; 1992 Apr.

10. Lin TH, LePage ME, Henzl M et al. Intranasal nafarelin: an LH-RH analogue treatment of gonadotropin-dependent precocious puberty. J Pediatr. 1986; 109:954-8. [IDIS 224961] [PubMed 2946840]

11. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Medical management of endometriosis. Practice Bulletin No. 11. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Dec 1999.

12. Pharmacia, Kalamazoo, MI: personal communication.

a. AHFS drug information 2008. McEvoy GK, ed. Nafarelin. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3174-5.

b. G.D. Searle LLC. Synarel (nafarelin acetate) nasal solution prescribing information for endometriosis. New York, NY; 2005 Aug.

c. G.D. Searle LLC. Synarel (nafarelin acetate) nasal solution patient information for endometriosis. New York, NY; 2007 Nov.

d. G.D. Searle LLC. Synarel (nafarelin acetate) nasal solution prescribing information for central precocious puberty. New York, NY; 2005 Jul.

e. G.D. Searle LLC. Synarel (nafarelin acetate) nasal solution patient information for central precocious puberty. New York, NY; 2007 Nov.

More Synarel resources

• Synarel Side Effects (in more detail)
• Synarel Use in Pregnancy & Breastfeeding
• Synarel Support Group
• 2 Reviews for Synarel - Add your own review/rating

• Synarel Prescribing Information (FDA)


• Synarel Concise Consumer Information (Cerner Multum)


• Synarel Advanced Consumer (Micromedex) - Includes Dosage Information


• Synarel MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Synarel with other medications

• Endometriosis
• Precocious Puberty