Synarel Information
Synarel (Nafarelin) Description
Synarel (Nafarelin) (nafarelin acetate) Nasal Solution is intended for administration as a spray to the nasal mucosa. Nafarelin acetate, the active component of Synarel (Nafarelin) Nasal Solution, is a decapeptide with the chemical name: 5-oxo--prolyl--histidyl--tryptophyl--seryl--tyrosyl-3-(2-naphthyl)--alanyl--leucyl--arginyl--prolyl-glycinamide acetate. Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH).
Nafarelin acetate has the following chemical structure:
Synarel (Nafarelin) Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for Synarel (Nafarelin) , each actuation of the unit delivers approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The contents of one spray bottle are intended to deliver at least 60 sprays.
Synarel (Nafarelin) Clinical Pharmacology
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 , 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 , 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 (Nafarelin) in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean C levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of C-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 C 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-NH(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 (Nafarelin) ; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel (Nafarelin) , the decongestant should not be used until at least 2 hours following dosing with Synarel (Nafarelin) .
When used regularly in girls and boys with at the recommended dose, Synarel (Nafarelin) 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 (
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 (Nafarelin) . 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 (Nafarelin) 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.
Synarel (Nafarelin) Warnings
Some patients may not show suppression of the pituitary-gonadal axis by clinical and/or biochemical parameters. This may be due to lack of compliance with the recommended treatment regimen and may be rectified by recommending that the dosing be done by caregivers. If compliance problems are excluded, the possibility of gonadotropin independent sexual precocity should be reconsidered and appropriate examinations should be conducted. If compliance problems are excluded and if gonadotropin independent sexual precocity is not present, the dose of Synarel (Nafarelin) may be increased to 1800 µg/day administered as 600 µg tid.
Synarel (Nafarelin) Precautions
An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information:
Sneezing during or immediately after dosing with Synarel (Nafarelin) should be avoided, if possible, since this may impair drug absorption.
Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential.
Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.
Synarel (Nafarelin) Adverse Reactions
In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus.
In these 155 patients treated for an average of 41 months and as long as 80 months (6.7 years), adverse events most frequently reported (>3% of patients) consisted largely of episodes occurring during the first 6 weeks of treatment as a result of the transient stimulatory action of nafarelin upon the pituitary-gonadal axis:
Hot flashes, common in adult women treated for endometriosis, occurred in only 3% of treated children and were transient. Other adverse events thought to be drug-related, and occurring in >3% of patients were rhinitis (5%) and white or brownish vaginal discharge (3%). Approximately 3% of patients withdrew from clinical trials due to adverse events.
In one male patient with concomitant congenital adrenal hyperplasia, and who had discontinued treatment 8 months previously to resume puberty, adrenal rest tumors were found in the left testis. Relationship to Synarel (Nafarelin) is unlikely.
Regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or computer assisted tomography (CT) of children during long-term nafarelin therapy as well as during the post-treatment period has occasionally revealed changes in the shape and size of the pituitary gland. These changes include asymmetry and enlargement of the pituitary gland, and a pituitary microadenoma has been suspected in a few children. The relationship of these findings to Synarel (Nafarelin) is not known.
Synarel (Nafarelin) Overdosage
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.
Based on studies in monkeys, Synarel (Nafarelin) is not absorbed after oral administration.
Synarel (Nafarelin) Dosage And Administration
For the treatment of central precocious puberty (CPP), the recommended daily dose of Synarel (Nafarelin) is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day.
The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays.
If the prescribed therapy has been well tolerated by the patient, treatment of CPP with Synarel (Nafarelin) should continue until resumption of puberty is desired.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of Synarel (Nafarelin) ; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel (Nafarelin) , the decongestant should not be used until at least 2 hours following dosing with Synarel (Nafarelin) .
Sneezing during or immediately after dosing with Synarel (Nafarelin) should be avoided, if possible, since this may impair drug absorption.
At 1600 µg/day, a bottle of Synarel (Nafarelin) provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy.
Synarel (Nafarelin) How Supplied
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL Synarel (Nafarelin) (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient instructions are also included.
Synarel (Nafarelin)
Synarel (Nafarelin) Description
Synarel (Nafarelin) (nafarelin acetate) Nasal Solution is intended for administration as a spray to the nasal mucosa. Nafarelin acetate, the active component of Synarel (Nafarelin) Nasal Solution, is a decapeptide with the chemical name: 5-oxo--prolyl--histidyl--tryptophyl--seryl--tyrosyl-3-(2-naphthyl)--alanyl--leucyl--arginyl--prolyl-glycinamide acetate. Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH).
Nafarelin acetate has the following chemical structure:
Synarel (Nafarelin) Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as nafarelin base) in a solution of benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water.
After priming the pump unit for Synarel (Nafarelin) , each actuation of the unit delivers approximately 100 µL of the spray containing approximately 200 µg nafarelin base. The contents of one spray bottle are intended to deliver at least 60 sprays.
Synarel (Nafarelin) Clinical Pharmacology
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 (Nafarelin) in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean C levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of C-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 C 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-NH(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 (Nafarelin) ; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel (Nafarelin) , the decongestant should not be used until at least 2 hours following dosing of Synarel (Nafarelin) .
In controlled clinical studies, Synarel (Nafarelin) 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) (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 (Nafarelin) 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 (Nafarelin) , 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 (Nafarelin) , 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) .
Synarel (Nafarelin) Indications And Usage For Endometriosis
(For Central Precocious Puberty, See )
Synarel (Nafarelin) is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with Synarel (Nafarelin) for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.
Synarel (Nafarelin) Warnings
When used regularly at the recommended dose, Synarel (Nafarelin) usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking Synarel (Nafarelin) , particularly if patients miss successive doses. Therefore, patients should use nonhormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.
Synarel (Nafarelin) Precautions
Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 µg/kg/day and mice (18 months) at doses up to 500 µg/kg/day using intramuscular doses (up to 110 times and 560 times the maximum recommended human intranasal dose, respectively). These multiples of the human dose are based on the relative bioavailability of the drug by the two routes of administration. As seen with other GnRH agonists, nafarelin acetate given to laboratory rodents at high doses for prolonged periods induced proliferative responses (hyperplasia and/or neoplasia) of endocrine organs. At 24 months, there was an increase in the incidence of pituitary tumors (adenoma/carcinoma) in high-dose female rats and a dose-related increase in male rats. There was an increase in pancreatic islet cell adenomas in both sexes, and in benign testicular and ovarian tumors in the treated groups. There was a dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was a dose-related increase in Harderian gland tumors in males and an increase in pituitary adenomas in high-dose females. No metastases of these tumors were observed. It is known that tumorigenicity in rodents is particularly sensitive to hormonal stimulation.
Mutagenicity studies were performed with nafarelin acetate using bacterial, yeast, and mammalian systems. These studies provided no evidence of mutagenic potential.
Reproduction studies in male and female rats have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to 6 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.
Synarel (Nafarelin) Adverse Reactions
In formal clinical trials of 1509 healthy adult patients, symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus occurred in 3 patients (approximately 0.2%).
As would be expected with a drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.
In controlled studies comparing Synarel (Nafarelin) (400 µg/day) and danazol (600 or 800 mg/day), adverse reactions most frequently reported and thought to be drug-related are shown in the figure below:
In addition, less than 1% of patients experienced paresthesia, palpitations, chloasma, maculopapular rash, eye pain, asthenia, lactation, breast engorgement, and arthralgia.
After six months of treatment with Synarel (Nafarelin) , vertebral trabecular bone density and total vertebral bone mass, measured by quantitative computed tomography (QCT), decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment levels. There was partial recovery of bone density in the post-treatment period; the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively. Total vertebral bone mass, measured by dual photon absorptiometry (DPA), decreased by a mean of 5.9% at the end of treatment.
After six months treatment with Synarel (Nafarelin) , bone mass as measured by dual x-ray bone densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by DEXA six months after completion of treatment, was 1.4% below pretreatment. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of Synarel (Nafarelin) for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.
Synarel (Nafarelin) Overdosage
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.
Based on studies in monkeys, Synarel (Nafarelin) is not absorbed after oral administration.
Synarel (Nafarelin) Dosage And Administration
For the management of endometriosis, the recommended daily dose of Synarel (Nafarelin) is 400 µg. This is achieved by one spray (200 µg) 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 (Nafarelin) 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. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with Synarel (Nafarelin) is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of Synarel (Nafarelin) ; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel (Nafarelin) , the decongestant should not be used until at least 2 hours following dosing with Synarel (Nafarelin) .
Sneezing during or immediately after dosing with Synarel (Nafarelin) should be avoided, if possible, since this may impair drug absorption.
At 400 µg/day, a bottle of Synarel (Nafarelin) provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy.
Synarel (Nafarelin) How Supplied
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL Synarel (Nafarelin) (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 µg of nafarelin per spray. A dust cover and a leaflet of patient instructions are also included.
Synarel (Nafarelin)
Synarel (Nafarelin)
Synarel (Nafarelin)
Synarel (Nafarelin) Principal Display Panel - Ml Label
NDC 0025-0166-08
SPRAY - FOR INTRANASAL USE ONLY.Each actuation delivers approximately200 mcg nafarelin.
Synarel (Nafarelin) Principal Display Panel - Ml Carton
NDC 0025-0166-08
SPRAY – FOR INTRANASAL USE ONLY
Each actuation delivers approximately200 mcg nafarelin.
Carton contains: 1 bottle of nasal solutionwith spray pump, patient information andcomplete prescribing information.
