Nafarelin

Nafarelin
Names
Trade namesSynarel, others
Other namesNafareline; Nafarelin acetate; RS-94991; RS-94991-298; [6-D-(2-naphthyl)alanine]-GnRH
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
Clinical data
Drug classGnRH analogue; GnRH agonist; antigonadotropin
Main usesEndometriosis, early puberty[1][2]
Side effectsWomen: Hot flushes, vaginal dryness, muscle pain, sexual dysfunction[1]
Kids: Acne, mood changes, increased pubic hair, vaginal bleeding[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • X
Routes of
use		Nasal spray[3][2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa601082
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
BioavailabilityIN: 2.8% (1.2–5.6%)[2]
Protein binding80%[2]
MetabolismPeptidases (not CYP450)[2]
Elimination half-lifeIN: 2.5–3.0 hours[2]
SC: 86 hours (metabolites)[2]
ExcretionUrine: 44–55%[2]
Feces: 19–44%[2]
Chemical and physical data
FormulaC66H83N17O13
Molar mass1322.496 g·mol−1
3D model (JSmol)
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 checkY
  • Key:RWHUEXWOYVBUCI-ITQXDASVSA-N checkY

Nafarelin, sold under the brand name Synarel among others, is a medication used to treat endometriosis and early puberty.[1][2] It is also used for uterine fibroids, as part of in vitro fertilization (IVF), and as part of transgender hormone therapy.[4][5][6] It is used as a nasal spray two to three times per day.[1]

Common side effects in women include hot flushes, vaginal dryness, muscle pain, and sexual dysfunction.[1] Common side effects in children include acne, mood changes, increased pubic hair, and vaginal bleeding.[1] Other side effects may include allergic reactions, osteoporosis, and pituitary apoplexy.[1] Use in pregnancy may harm the baby.[1] It is a gonadotropin-releasing hormone agonist (GnRH agonist) and works by briefly increasing than decreasing the production of sex hormones by the gonads.[2]

Nafarelin was approved for medical use in the United States in 1990.[1] In the United Kingdom 60 doses of 200 mcg cost the NHS about £50 as of 2021.[7] In the United States this amount costs about 2,800 USD.[8] It is available in many countries globally.[9] It is one of two GnRH analogues available as a nasal spray, the other being buserelin.[10]

Medical uses

Nafarelin is approved and used in the treatment of endometriosis and precocious puberty.[2][3] It is also used in the treatment of uterine fibroids.[4][11] The medication is used to control ovarian stimulation in in vitro fertilization (IVF).[12][13] Nafarelin is used as a puberty blocker in transgender youth and to suppress testosterone levels in transgender women.[14][6][15][16][17] Nafarelin can also be used to treat hirsutism and polycystic ovary syndrome by lowering gonadotropin and androgen levels.[3][11][18] It is effective in the treatment of benign prostatic hyperplasia.[3]

Dosage

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 μg/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.[19][2][3] 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.[20]

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.[21] 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.[22] There is a case report of severe hyperkalemia during nafarelin therapy in a woman with uterine fibroids.[23] The mechanism is unknown.[23]

Pharmacology

Pharmacodynamics

Nafarelin is a GnRH agonist, or an agonist of the GnRH receptor, the biological target of GnRH.[3][2] It works by continuously activating the GnRH receptor, which results in profound desensitization of the receptor such that it becomes non-functional.[3][2] As a result, nafarelin suppresses the GnRH-induced secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland.[3][2] This, in turn, results in profound suppression of gonadal sex hormone production, as well as reversible suppression of fertility.[3][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.[3][2][20] It is a decapeptide and is also known as [6-D-(2-naphthyl)alanine]-GnRH.[20][24] Nafarelin is marketed for medical use in both its free base (nafarelin) and acetate salt (nafarelin acetate) forms.[9]

History

Nafarelin was introduced for medical use in 1990.[25][3][26]

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.[27][9][28][29] It is also known by its former developmental code name RS-94991 or RS-94991-298.[27][9][28][29]

Brand names

The major brand names of nafarelin are Synarel and Synarela.[9][29] It has also been marketed under a number of other brand names including Synrelin, Synrelina, Nafarelil 0.2%, and Nasanyl 0.2%.[9][29]

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.[9][29]

See also

  • Gonadotropin-releasing hormone receptor § Agonists

References

  1. 1 2 3 4 5 6 7 8 9 10 "Nafarelin Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2021. Retrieved 11 November 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 "DailyMed - SYNAREL- nafarelin acetate spray, metered". dailymed.nlm.nih.gov. Archived from the original on 30 March 2021. Retrieved 11 November 2021.
  3. 1 2 3 4 5 6 7 8 9 10 11 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.
  4. 1 2 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.
  5. ↑ Elder, Kay; Dale, Brian (2 December 2010). In-Vitro Fertilization. Cambridge University Press. p. 24. ISBN 978-1-139-49285-0. Archived from the original on 13 November 2021. Retrieved 11 November 2021.
  6. 1 2 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.
  7. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 782. ISBN 978-0857114105.
  8. ↑ "Nafarelin Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 11 November 2021.
  9. 1 2 3 4 5 6 7 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 712–. ISBN 978-3-88763-075-1. Archived from the original on 2021-10-28. Retrieved 2021-08-23.
  10. ↑ 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. Archived from the original on 28 October 2021. Retrieved 23 August 2021.
  11. 1 2 Monroe SE, Andreyko J (December 1989). "Treatment of uterine leiomyomas and hirsutism with nafarelin". J Reprod Med. 34 (12 Suppl): 1029–33. PMID 2533618.
  12. ↑ Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in Deutsch) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 372–3. ISBN 3-8047-1763-2.
  13. ↑ 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. Archived from the original on 2015-12-08. Retrieved 2021-08-23.
  14. ↑ 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. ISBN 978-3-319-73781-2.
  15. ↑ 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.
  16. ↑ Spack NP (February 2013). "Management of transgenderism". JAMA. 309 (5): 478–84. doi:10.1001/jama.2012.165234. PMID 23385274.
  17. ↑ 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. S2CID 73253356.
  18. ↑ 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.
  19. ↑ 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. Archived from the original on 28 October 2021. Retrieved 23 August 2021.
  20. 1 2 3 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. Archived from the original on 28 October 2021. Retrieved 23 August 2021.
  21. ↑ Munarriz, Ricardo; Traish, Abdul (2009). "Impact of Androgen Deprivation on Male Sexual Function". Sexual Function in the Prostate Cancer Patient. pp. 163–175. doi:10.1007/978-1-60327-555-2_11. ISBN 978-1-60327-554-5.
  22. ↑ DailyMed: Synarel – nafarelin acetate spray Archived 2014-03-30 at the Wayback Machine
  23. 1 2 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. S2CID 39987508.
  24. ↑ 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.
  25. ↑ "Drugs@FDA: FDA-Approved Drugs". Archived from the original on 2021-03-23. Retrieved 2021-08-23.
  26. ↑ 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.
  27. 1 2 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. Archived from the original on 28 October 2021. Retrieved 23 August 2021.
  28. 1 2 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.
  29. 1 2 3 4 5 "Nafarelin nasal Uses, Side Effects & Warnings". Archived from the original on 2018-08-28. Retrieved 2021-08-23.
Identifiers:
  • 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.
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