Synarel
Synarel - General Information
A potent synthetic agonist of gonadotropin-releasing hormone with 3-(2-naphthyl)-D-alanine substitution at residue 6. Synarel has been used in the treatments of central precocious puberty and endometriosis. [PubChem]
Pharmacology of Synarel
Synarel is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, LH and FSH, resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. After nafarelin therapy is discontinued, pituitary and ovarian function normalize and estradiol serum concentrations increase to pretreatment levels. Recurrences of endometriosis are frequent after cessation of any hormonal therapy and after surgery that leaves the ovaries and/or uterus intact.
Synarel for patients
An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information:
- Reversibility of the suppressive effects of nafarelin has been demonstrated by the appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex steroid levels, and/or by advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documented by pregnancies and the effect of long-term use of the drug on fertility is not known.
- Patients and their caregivers should be adequately counseled to assure full compliance; irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.
- During the first month of treatment with SYNAREL, some signs of puberty, e.g., vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of the drug. Such changes should resolve soon after the first month. lf such resolution does not occur within the first two months of treatment, this may be due to lack of compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are definitively excluded, the dose of SYNAREL may be increased to 1800 µg/day administered as 600 µg TID.
- Patients with intercurrent rhinitis should consult their physician for the use of a topical nasal decongestant. If the use of a topical nasal decongestant is required during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption.
Synarel Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with SYNAREL. However, because nafarelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes, and the drug is only about 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur.
Synarel Contraindications
- Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in SYNAREL;
- Undiagnosed abnormal vaginal bleeding;
- Use in pregnancy or in women who may become pregnant while receiving the drug. SYNAREL may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rats, but not in mice or rabbits after administration of SYNAREL during the period of organogenesis. There was a dose-related increase in fetal mortality and a decrease in fetal weight in rats. The effects on rat fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus;
- Use in women who are breast-feeding.
Additional information about Synarel
Synarel Indication: For treatment of gonadotropin-dependent precocious puberty in children of both sexes and for the treatment of endometriosis.
Mechanism Of Action: Like GnRH, initial or intermittent administration of nafarelin stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor. A reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes occur. This causes a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes. Like normal endometrium, endometriotic implants contain estrogen receptors. Estrogen stimulates the growth of endometrium. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants. Synarel does not abolish the underlying pathophysiology of endometriosis, however.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Nafarelin
Synonyms: Nafarelin acetate
Drug Category: Gonadotropin-releasing hormones; Antiendometriotic agent
Drug Type: Small Molecule; Approved
Other Brand Names containing Nafarelin: Synarel;
Absorption: Rapidly absorbed into the systemic circulation after intranasal administration. Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). Not absorbed after oral administration.
Toxicity (Overdose): In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs.
Protein Binding: Approximately 80%.
Biotransformation: Enzymatic hydrolysis.
Half Life: 3 hours
Dosage Forms of Synarel: Aerosol, metered Nasal
Chemical IUPAC Name: N-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide
Chemical Formula: C66H83N17O13
Nafarelin on Wikipedia: https://en.wikipedia.org/wiki/Nafarelin
Organisms Affected: Humans and other mammals