Recommended Dose and Dosage Adjustment For the management of endometriosis, the recommended daily dose of Synarel (nafarelin acetate) is 400 μg. This is achieved by one spray (200 μg of nafarelin free base) into one nostril in the morning and one spray into the other nostril in the evening.
Treatment should be started between days 2 and 4 of the menstrual cycle. In an occasional patient, the 400 μg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of Synarel may be increased to 800 μg daily.
The 800 μg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. The recommended duration of administration is six months. The safety of retreatment as well as of treatment beyond 6 months with nafarelin has not yet been established.
If the symptoms of endometriosis recur after a course of therapy, and further treatment with Synarel is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
If the use of a topical nasal decongestant is necessary during treatment with Synarel, the decongestant should not be used until at least 30 minutes after Synarel dosing (see DRUG INTERACTIONS). At 400 μg/day, an 8 mL bottle of Synarel provides a 30 day supply (about 60 sprays).
If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre.
12 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Nafarelin is an agonistic analogue of the gonadotropin releasing hormone (GnRH). Given as a single intranasal dose, nafarelin stimulates release of the pituitary gonadotropins, LH and FSH, with consequent increase of ovarian steroidogenesis.
Repeated intranasal dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration of 200 μg, as a nasal spray, 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.
Pharmacodynamics General The effects of a single 500 μg IN dose of nafarelin on the secretion of LH were investigated in six women who previously had had hysterectomies. 5 μg given at approximately weekly intervals. Serum LH concentrations increased to peak levels 5- to 40-fold higher than predosing baseline levels after 500 μg IN nafarelin.
Serum LH levels also increased in response to each of the lower doses in at least three of the four women. 5 μg dose, thus indicating that the analog was extremely potent in that very low concentrations (< 50 pg/mL) were sufficient to stimulate the release of LH.
Most importantly this study demonstrated that nasal administration of nafarelin might be suitable for clinical applications. Gonadotropin-Ovarian Responses to 90 or 180 Day Administration of Intranasal Nafarelin In a single-center, open, parallel, nonrandomized investigation, fifteen healthy volunteers were enrolled to study ovulation inhibition (Part A) and nine additional women with endometriosis were enrolled to study their gonadotropin-ovarian response (Part B).
Four doses of IN nafarelin (formulated at three different concentrations) were employed. 5 mg/mL spray) daily for three months. 5 mg/mL, expressed as the acetate salt) of nafarelin twice a day for six months. A dose of 500 μg of nafarelin acetate corresponds to a 400 μg dose of nafarelin base.
In all women receiving nafarelin once a day there was little, or at most, inconsistent desensitization of pituitary gonadotropes. There was generally a large, acute increase in serum gonadotropin levels after each dose of nafarelin, which peaked within 2 to 4 hours.
In most instances, the acute release of LH and FSH induced a similar, but somewhat delayed, increase in serum concentrations of E2. Although there was only partial pituitary desensitization, some dose-dependent changes in ovarian function were observed.
Mean E2 concentrations during the third treatment month were either comparable to (125 and 250 μg dose groups) or below (500 μg dose group) pretreatment values. 13 The pituitary responses to 1000 μg nafarelin (500 μg twice a day) were quite different.
There was a small, but significant, decrease in basal levels of both LH and FSH. In addition, there was almost complete desensitization of the pituitary gonadotropes with only small and inconsistent increases in serum levels of LH and FSH in response to drug administration.
Mean basal concentrations of E2 decreased to less than 30 pg/mL by the fourth week of treatment. The effects of nafarelin administration upon ovulatory ovarian function were dose related. Inhibition of ovulation correlated with the degree of suppression of estradiol secretion.
, women receiving 1000 μg nafarelin/day), ovulation was reliably inhibited. The most common complaint in the women receiving nafarelin, hot flashes, resulted from hypoestrogenemia. They were reported by one subject in each of the 125, 250, and 500 μg/day groups and by all patients receiving 1000 μg/day.
Effects of 500 μg of Nafarelin Acetate Every 12 Hours Upon Endometriosis The effects of nafarelin treatment on the symptoms and severity of endometriosis (measured according to the American Fertility Society scoring system) were assessed in the patients in Part B of the clinical study described above.
There was a […]