Nafarelin

Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in the treatment of endometriosis and early puberty.[1][2] It is also used to treat uterine fibroids, to control ovarian stimulation in in vitro fertilization (IVF), and as part of transgender hormone therapy.[3][4][5][6] The medication is used as a nasal spray two to three times per day.[1][2][7]

Nafarelin

Clinical data
Trade names	Synarel, others
Other names	Nafareline; Nafarelin acetate; RS-94991; RS-94991-298; [6-D-(2-naphthyl)alanine]-GnRH
AHFS/Drugs.com	Monograph
MedlinePlus	a601082
Pregnancy category	X
Routes of administration	Nasal spray[1][2]
Drug class	GnRH analogue; GnRH agonist; Antigonadotropin
ATC code	H01CA02 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	IN: 2.8% (1.2–5.6%)[2]
Protein binding	80%[2]
Metabolism	Peptidases (not CYP450)[2]
Elimination half-life	IN: 2.5–3.0 hours[2] SC: 86 hours (metabolites)[2]
Excretion	Urine: 44–55%[2] Feces: 19–44%[2]
Identifiers
IUPAC name (2R)-N-[(2R)-5-carbamimidamido-1-[(2S)-2-[(carbamoylmethyl)carbamoyl]pyrrolidin-1-yl]-1-oxopentan-2-yl]-2-[(2R)-2-[(2R)-2-[(2R)-3-hydroxy-2-[(2S)-2-[(2S)-3-(1H-imidazol-4-yl)-2-{[(2R)-5-oxopyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-3-yl)propanamido]propanamido]-3-(4-hydroxyphenyl)propanamido]-3-(naphthalen-2-yl)propanamido]-4-methylpentanamide
CAS Number	76932-56-4^Y 76932-60-0 (acetate)
PubChem CID	25077649
IUPHAR/BPS	3902
DrugBank	DB00666^Y
ChemSpider	10482014^Y
UNII	1X0094V6JV
KEGG	D08241
ChEBI	CHEBI:7445^Y
ChEMBL	ChEMBL1201309^Y
ECHA InfoCard	100.212.186
Chemical and physical data
Formula	C66H83N17O13
Molar mass	1322.496 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CC(C)C[C@@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N)NC(=O)[C@@H](CC2=CC3=CC=CC=C3C=C2)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC5=CNC6=CC=CC=C65)NC(=O)[C@H](CC7=CNC=N7)NC(=O)[C@@H]8CCC(=O)N8
InChI InChI=1S/C66H83N17O13/c1-36(2)25-48(58(89)76-47(13-7-23-71-66(68)69)65(96)83-24-8-14-54(83)64(95)73-33-55(67)86)77-60(91)50(28-38-15-18-39-9-3-4-10-40(39)26-38)78-59(90)49(27-37-16-19-43(85)20-17-37)79-63(94)53(34-84)82-61(92)51(29-41-31-72-45-12-6-5-11-44(41)45)80-62(93)52(30-42-32-70-35-74-42)81-57(88)46-21-22-56(87)75-46/h3-6,9-12,15-20,26,31-32,35-36,46-54,72,84-85H,7-8,13-14,21-25,27-30,33-34H2,1-2H3,(H2,67,86)(H,70,74)(H,73,95)(H,75,87)(H,76,89)(H,77,91)(H,78,90)(H,79,94)(H,80,93)(H,81,88)(H,82,92)(H4,68,69,71)/t46-,47-,48-,49-,50+,51-,52-,53-,54-/m0/s1^Y Key:RWHUEXWOYVBUCI-ITQXDASVSA-N^Y
(verify)

Side effects of nafarelin are related to sex hormone deprivation and include symptoms of low testosterone levels and low estrogen levels such as hot flashes, sexual dysfunction, vaginal atrophy, and osteoporosis.[2] Nafarelin is a gonadotropin-releasing hormone agonist (GnRH agonist) and works by preventing the production of sex hormones by the gonads.[1][2] It can lower sex hormone levels by 95% in both sexes.[1][2] Nafarelin is a peptide and an analogue of GnRH.[8]

Nafarelin was introduced for medical use in 1990.[9][1][10] It is available widely throughout the world, including in North America, Europe, and elsewhere throughout the world.[11][12] The medication is one of only two medically used GnRH analogues that are available as nasal sprays, the other being buserelin.[13]

Medical uses

Nafarelin is approved and used in the treatment of endometriosis and precocious puberty.[2][1] It is also used in the treatment of uterine fibroids.[3][14] The medication is used to control ovarian stimulation in in vitro fertilization (IVF).[4][15] Nafarelin is used as a puberty blocker in transgender youth and to suppress testosterone levels in transgender women.[16][5][17][6][18] Nafarelin can also be used to treat hirsutism and polycystic ovary syndrome by lowering gonadotropin and androgen levels.[1][14][19] It is effective in the treatment of benign prostatic hyperplasia.[1]

Dosages

Nafarelin is used to treat precocious puberty at a dosage of 1,600 to 1,800 μg per day.[2] The 1,600 μg/day dosage is achieved by two sprays (400 μg total) into each nostril in the morning (four sprays, 800 μg total) and two sprays (400 μg total) into each nostril in the evening (four sprays, 800 μg total).[2] If 1,600 mg/day is insufficient for adequate pubertal suppression, the 1,800 μg/day dosage can be used instead. This is achieved by three sprays (600 μg total) into alternating nostrils three times per day (nine sprays per day total).[2] When administering the sprays, the head should be tilted back slightly and 30 seconds should elapse between each spray.[2] A bottle of nafarelin nasal spray (brand name Synarel) lasts for about 7 days at a dosage of 1,600 μg/day.[2]

Nafarelin is used to treat endometriosis at lower dosages of 400 to 800 μg per day.[2] This is achieved by one or two sprays (200 or 400 μg total) into alternating nostrils once in the morning and once in the evening (two to four sprays per day total).[2] A bottle of nafarelin nasal spray (brand name Synarel) lasts for about 30 days at a dosage of 400 μg/day.[2]

Available forms

Nafarelin is available in the form of a 0.2% nasal spray for use one, two, or three times per day.[20][2][1] Each bottle of nafarelin nasal spray (brand name Synarel) contains about 60 sprays delivering approximately 200 μg nafarelin in 100 μL solution per actuation.[2] Nafarelin is not available for use by any other routes than intranasal administration.[21]

Side effects

Side effects of nafarelin are related to sex hormone deficiency and include hot flashes, vaginal dryness, headaches, mood changes, and sexual dysfunction. Nafarelin causes erectile dysfunction in more than half of men with benign prostatic hyperplasia treated with it.[22] Some people may experience acne, muscle pain, reduced breast size, and nasal irritation. These side effects are reversible and should resolve after stopping the medication.[23] There is a case report of severe hyperkalemia during nafarelin therapy in a woman with uterine fibroids.[24] The mechanism is unknown.[24]

Pharmacology

Pharmacodynamics

Nafarelin is a GnRH agonist, or an agonist of the GnRH receptor, the biological target of GnRH.[1][2] It works by continuously activating the GnRH receptor, which results in profound desensitization of the receptor such that it becomes non-functional.[1][2] As a result, nafarelin suppresses the GnRH-induced secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland.[1][2] This, in turn, results in profound suppression of gonadal sex hormone production, as well as reversible suppression of fertility.[1][2]

Pharmacokinetics

The bioavailability of nafarelin with intranasal administration is 2.8% on average, with a range of 1.2 to 5.6%.[2] The plasma protein binding of nafarelin is 80%.[2] It is metabolized primarily by peptidases and not by cytochrome P450 enzymes.[2] The elimination half-life of nafarelin is 2.5 to 3.0 hours by intranasal administration, whereas the half-life of nafarelin and its metabolites by subcutaneous injection is 85.5 hours.[2] Nafarelin is eliminated 44 to 55% in urine and 18.5 to 44.2% in feces.[2]

Chemistry

Nafarelin is a GnRH analogue, or a synthetic analogue of GnRH.[1][2][21] It is a decapeptide and is also known as [6-D-(2-naphthyl)alanine]-GnRH.[21][25] Nafarelin is marketed for medical use in both its free base (nafarelin) and acetate salt (nafarelin acetate) forms.[12]

History

Nafarelin was introduced for medical use in 1990.[9][1][10]

Society and culture

Generic names

Nafarelin is the generic name of the drug and its INN and BAN, while nafaréline is its DCF and nafarelin acetate is its USAN, BANM, and JAN.[26][12][27][11] It is also known by its former developmental code name RS-94991 or RS-94991-298.[26][12][27][11]

Brand names

The major brand names of nafarelin are Synarel and Synarela.[12][11] It has also been marketed under a number of other brand names including Synrelin, Synrelina, Nafarelil 0.2%, and Nasanyl 0.2%.[12][11]

Availability

Nafarelin is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, other European countries, Australia, Israel, Argentina, Brazil, Mexico, and Japan.[12][11]

See also

• Gonadotropin-releasing hormone receptor § Agonists

References

1. Chrisp P, Goa KL (April 1990). "Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions". Drugs. 39 (4): 523–51. doi:10.2165/00003495-199039040-00005. PMID 2140979.
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019886s033s035lbl.pdf
3. Minaguchi H, Wong JM, Snabes MC (June 2000). "Clinical use of nafarelin in the treatment of leiomyomas. A review of the literature". J Reprod Med. 45 (6): 481–9. PMID 10900582.
4. Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 372–3. ISBN 3-8047-1763-2.
5. Olshan J, Eimicke T, Belfort E (June 2016). "Gender Incongruity in Children With and Without Disorders of Sexual Differentiation". Endocrinol. Metab. Clin. North Am. 45 (2): 463–82. doi:10.1016/j.ecl.2016.02.001. PMID 27241976.
6. Spack NP (February 2013). "Management of transgenderism". JAMA. 309 (5): 478–84. doi:10.1001/jama.2012.165234. PMID 23385274.
7. Magon N (October 2011). "Gonadotropin releasing hormone agonists: Expanding vistas". Indian J Endocrinol Metab. 15 (4): 261–7. doi:10.4103/2230-8210.85575. PMC 3193774. PMID 22028996.
8. Ved Srivastava (26 June 2017). Peptide-based Drug Discovery: Challenges and New Therapeutics. Royal Society of Chemistry. pp. 182–. ISBN 978-1-78262-732-6.
9. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019886
10. Conn PM, Crowley WF (January 1991). "Gonadotropin-releasing hormone and its analogues". N. Engl. J. Med. 324 (2): 93–103. doi:10.1056/NEJM199101103240205. PMID 1984190.
11. https://www.drugs.com/international/nafarelin.html
12. Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 712–. ISBN 978-3-88763-075-1.
13. T. Metin Önerci (17 August 2013). Nasal Physiology and Pathophysiology of Nasal Disorders. Springer Science & Business Media. pp. 208–. ISBN 978-3-642-37250-6.
14. Monroe SE, Andreyko J (December 1989). "Treatment of uterine leiomyomas and hirsutism with nafarelin". J Reprod Med. 34 (12 Suppl): 1029–33. PMID 2533618.
15. Wuttke, W; Jarry, H; Feleder, C; Moguilevsky, J; Leonhardt, S; Seong, J. Y.; Kim, K (1996). "The neurochemistry of the GnRH pulse generator". Acta neurobiologiae experimentalis. 56 (3): 707–13. PMID 8917899.
16. Lee, Janet Y.; Perl, Liat; Rosenthal, Stephen M. (2018). "Care of Gender Nonconforming/Transgender Youth". Pediatric Endocrinology: 813–823. doi:10.1007/978-3-319-73782-9_36.
17. Olson J, Garofalo R (June 2014). "The peripubertal gender-dysphoric child: puberty suppression and treatment paradigms". Pediatr Ann. 43 (6): e132–7. doi:10.3928/00904481-20140522-08. PMID 24972421.
18. Nakatsuka, Mikiya (2014). "Endocrine treatment of transsexuals: assessment of cardiovascular risk factors". Expert Review of Endocrinology & Metabolism. 5 (3): 319–322. doi:10.1586/eem.10.18. ISSN 1744-6651. PMID 30861686.
19. Shaw RW (June 1988). "GnRH agonists-antagonists--clinical applications". Eur. J. Obstet. Gynecol. Reprod. Biol. 28 (2): 109–16. doi:10.1016/0028-2243(88)90086-X. PMID 2969835.
20. Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 230–. ISBN 978-1-60913-345-0.
21. Tommaso Falcone; William W. Hurd (14 June 2017). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer. pp. 9–. ISBN 978-3-319-52210-4.
22. Munarriz, Ricardo; Traish, Abdul (2009). "Impact of Androgen Deprivation on Male Sexual Function": 163–175. doi:10.1007/978-1-60327-555-2_11. Cite journal requires |journal= (help)
23. DailyMed: Synarel – nafarelin acetate spray
24. Hata T, Hata K, Kawamura T (February 1996). "Severe hyperkalaemia with nafarelin". Lancet. 347 (8997): 333. doi:10.1016/S0140-6736(96)90514-0. PMID 8569395.
25. Kreuser ED, Klingmüller D, Thiel E (1993). "The role of LHRH-analogues in protecting gonadal functions during chemotherapy and irradiation". Eur. Urol. 23 (1): 157–63, discussion 163–4. doi:10.1159/000474586. PMID 8477775.
26. J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 846–. ISBN 978-1-4757-2085-3.
27. I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 189–. ISBN 978-94-011-4439-1.

Further reading

• Barbieri RL (February 1990). "Comparison of the pharmacology of nafarelin and danazol". Am. J. Obstet. Gynecol. 162 (2): 581–5. doi:10.1016/0002-9378(90)90436-B. PMID 2137975.
• Chrisp P, Goa KL (April 1990). "Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions". Drugs. 39 (4): 523–51. doi:10.2165/00003495-199039040-00005. PMID 2140979.
• Burry KA (February 1992). "Nafarelin in the management of endometriosis: quality of life assessment". Am. J. Obstet. Gynecol. 166 (2): 735–9. doi:10.1016/0002-9378(92)91705-F. PMID 1531576.
• Minaguchi H, Wong JM, Snabes MC (June 2000). "Clinical use of nafarelin in the treatment of leiomyomas. A review of the literature". J Reprod Med. 45 (6): 481–9. PMID 10900582.