Nafarelin acetate 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.
In children, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of a 400 µg dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given a dose above 600 µg.
In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately 3 hours. About 80% of nafarelin acetate was bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5–10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL.
When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects a corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter, menstruation should cease.
In clinical studies the peak response of LH to GnRH stimulation was reduced from a pubertal response to a prepubertal response (<15 mlU/mL) within one month of treatment.
Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in most children within the first year of treatment to values of 5 to 6 cm/year or less. Children with CPP are frequently taller than their chronological age peers; height for chronological age approaches normal in most children during the second or third year of treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone age divided by change in chronological age) is usually abnormal (greater than 1) in children with CPP; in most children, bone age velocity approaches normal (1) during the first year of treatment. This results in a narrowing of the gap between bone age and chronological age, usually by the second or third year of treatment. The mean predicted adult height increases.
In clinical trials, breast development was arrested or regressed in 82% of girls, and genital development was arrested or regressed in 100% of boys. Because pubic hair growth is largely controlled by adrenal androgens, which are unaffected by nafarelin, pubic hair development was arrested or regressed only in 54% of girls and boys.
Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all children with CPP for whom one-year post-treatment follow-up is available (n=69). This demonstration consisted of the appearance or return of menses, the return of pubertal gonadotropin and gonadal sex steroid levels, and/or the 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.
Nafarelin acetate 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 ovarian 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.
Nafarelin acetate is rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration is approximately 3 hours. About 80% of nafarelin acetate is bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5–10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing of SYNAREL.
In controlled clinical studies, SYNAREL at doses of 400 and 800 µg/day for 6 months was shown to be comparable to danazol, 800 mg/day, in relieving the clinical symptoms of endometriosis (pelvic pain, dysmenorrhea, and dyspareunia) and in reducing the size of endometrial implants as determined by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time and, in addition, laparoscopic staging of endometriosis does not necessarily correlate with severity of symptoms.
In a single controlled clinical trial, intranasal SYNAREL (nafarelin acetate) at a dose of 400 µg per day was shown to be clinically comparable to intramuscular leuprolide depot, 3.75 mg monthly, for the treatment of the symptoms (dysmenorrhea, dyspareunia and pelvic pain) associated with endometriosis.
SYNAREL 400 µg daily induced amenorrhea in approximately 65%, 80%, and 90% of the patients after 60, 90, and 120 days, respectively. In the first, second, and third post-treatment months, normal menstrual cycles resumed in 4%, 82%, and 100%, respectively, of those patients who did not become pregnant.
At the end of treatment, 60% of patients who received SYNAREL, 400 µg/day, were symptom free, 32% had mild symptoms, 7% had moderate symptoms, and 1% had severe symptoms. Of the 60% of patients who had complete relief of symptoms at the end of treatment, 17% had moderate symptoms 6 months after treatment was discontinued, 33% had mild symptoms, 50% remained symptom free, and no patient had severe symptoms.
During the first two months use of SYNAREL, some women experience vaginal bleeding of variable duration and intensity. In all likelihood, this bleeding represents estrogen withdrawal bleeding and is expected to stop spontaneously. If vaginal bleeding continues, the possibility of lack of compliance with the dosing regimen should be considered. If the patient is complying carefully with the regimen, an increase in dose to 400 µg twice a day should be considered.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of SYNAREL.
Nafarelin acetate 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.
In children, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 45 minutes. Following a single dose of 400 µg base, the observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 µg base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of a 400 µg dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given a dose above 600 µg.
In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately 3 hours. About 80% of nafarelin acetate was bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5–10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing with SYNAREL.
When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects a corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter, menstruation should cease.
In clinical studies the peak response of LH to GnRH stimulation was reduced from a pubertal response to a prepubertal response (<15 mlU/mL) within one month of treatment.
Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in most children within the first year of treatment to values of 5 to 6 cm/year or less. Children with CPP are frequently taller than their chronological age peers; height for chronological age approaches normal in most children during the second or third year of treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone age divided by change in chronological age) is usually abnormal (greater than 1) in children with CPP; in most children, bone age velocity approaches normal (1) during the first year of treatment. This results in a narrowing of the gap between bone age and chronological age, usually by the second or third year of treatment. The mean predicted adult height increases.
In clinical trials, breast development was arrested or regressed in 82% of girls, and genital development was arrested or regressed in 100% of boys. Because pubic hair growth is largely controlled by adrenal androgens, which are unaffected by nafarelin, pubic hair development was arrested or regressed only in 54% of girls and boys.
Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all children with CPP for whom one-year post-treatment follow-up is available (n=69). This demonstration consisted of the appearance or return of menses, the return of pubertal gonadotropin and gonadal sex steroid levels, and/or the 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.
Nafarelin acetate 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 ovarian 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.
Nafarelin acetate is rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 µg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 µg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration is approximately 3 hours. About 80% of nafarelin acetate is bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 µg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5–10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacokinetics of the drug in hepatically- and renally-impaired patients have not been determined.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the decongestant should not be used until at least 2 hours following dosing of SYNAREL.
In controlled clinical studies, SYNAREL at doses of 400 and 800 µg/day for 6 months was shown to be comparable to danazol, 800 mg/day, in relieving the clinical symptoms of endometriosis (pelvic pain, dysmenorrhea, and dyspareunia) and in reducing the size of endometrial implants as determined by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time and, in addition, laparoscopic staging of endometriosis does not necessarily correlate with severity of symptoms.
In a single controlled clinical trial, intranasal SYNAREL (nafarelin acetate) at a dose of 400 µg per day was shown to be clinically comparable to intramuscular leuprolide depot, 3.75 mg monthly, for the treatment of the symptoms (dysmenorrhea, dyspareunia and pelvic pain) associated with endometriosis.
SYNAREL 400 µg daily induced amenorrhea in approximately 65%, 80%, and 90% of the patients after 60, 90, and 120 days, respectively. In the first, second, and third post-treatment months, normal menstrual cycles resumed in 4%, 82%, and 100%, respectively, of those patients who did not become pregnant.
At the end of treatment, 60% of patients who received SYNAREL, 400 µg/day, were symptom free, 32% had mild symptoms, 7% had moderate symptoms, and 1% had severe symptoms. Of the 60% of patients who had complete relief of symptoms at the end of treatment, 17% had moderate symptoms 6 months after treatment was discontinued, 33% had mild symptoms, 50% remained symptom free, and no patient had severe symptoms.
During the first two months use of SYNAREL, some women experience vaginal bleeding of variable duration and intensity. In all likelihood, this bleeding represents estrogen withdrawal bleeding and is expected to stop spontaneously. If vaginal bleeding continues, the possibility of lack of compliance with the dosing regimen should be considered. If the patient is complying carefully with the regimen, an increase in dose to 400 µg twice a day should be considered.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of SYNAREL.
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