SYNAREL (nafarelin acetate) Nasal Solution is intended for administration as a spray to the nasal mucosa. Nafarelin acetate, the active component of SYNAREL Nasal Solution, is a decapeptide with the chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl- 3- (2-naphthyl) -D-alanyl-L-leucyl-L-arginyl-L-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 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, 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.
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 C min levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.
After subcutaneous administration of 14 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 14 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-GIy-NH 2 (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 mg 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.
(For Central Precocious Puberty, See Central Precocious Puberty section)
SYNAREL is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with SYNAREL for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.
Safe use of nafarelin acetate in pregnancy has not been established clinically. Before starting treatment with SYNAREL, pregnancy must be excluded.
When used regularly at the recommended dose, SYNAREL usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking SYNAREL, 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.
As with other drugs that stimulate the release of gonadotropins or that induce ovulation, ovarian cysts have been reported to occur in the first two months of therapy with SYNAREL. Many, but not all, of these events occurred in patients with polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by about four to six weeks of therapy, but in some cases may require discontinuation of drug and/or surgical intervention.
An information pamphlet for patients is included with the product. Patients should be aware of the following information:
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.
Administration of SYNAREL in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to 4 to 8 weeks after discontinuation of therapy with SYNAREL may be misleading.
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.
Pregnancy Category X. See 'CONTRAINDICATIONS.' Intramuscular SYNAREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 µg/kg/day (about 0.5, 2, and 7 times the maximum recommended human intranasal dose based on the relative bioavailability by the two routes of administration). An increase in major fetal abnormalities was observed in 4/80 fetuses at the highest dose. A similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 µg/kg/day and 0.18 µg/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was a dose-related increase in fetal mortality and a decrease in fetal weight with the highest dose.
It is not known whether SYNAREL is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of SYNAREL on lactation and/or the breast-fed child have not been determined, SYNAREL should not be used by nursing mothers.
Safety and effectiveness of SYNAREL for endometriosis in patients younger than 18 years have not been established.
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 (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, 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, 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 levels. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of SYNAREL 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.
Plasma enzymes . During clinical trials with SYNAREL, regular laboratory monitoring revealed that SGOT and SGPT levels were more than twice the upper limit of normal in only one patient each. There was no other clinical or laboratory evidence of abnormal liver function and levels returned to normal in both patients after treatment was stopped.
Lipids . At enrollment, 9% of the patients in the group taking SYNAREL 400 µg/day and 2% of the patients in the danazol group had total cholesterol values above 250 mg/dL. These patients also had cholesterol values above 250 mg/dL at the end of treatment.
Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in the group treated with SYNAREL and 18% in the danazol group, had post-treatment values above 250 mg/dL.
The mean (± SEM) pretreatment values for total cholesterol from all patients were 191.8 (4.3) mg/dL in the group treated with SYNAREL and 193.1 (4.6) mg/dL in the danazol group. At the end of treatment, the mean values for total cholesterol from all patients were 204.5 (4.8) mg/dL in the group treated with SYNAREL and 207.7 (5.1) mg/dL in the danazol group. These increases from the pretreatment values were statistically significant (p<0.05) in both groups.
Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients who received SYNAREL and in 7% of the patients who received danazol.
At the end of treatment, no patients receiving SYNAREL had abnormally low HDL cholesterol fractions (less than 30 mg/dL) compared with 43% of patients receiving danazol. None of the patients receiving SYNAREL had abnormally high LDL cholesterol fractions (greater than 190 mg/dL) compared with 15% of those receiving danazol. There was no increase in the LDL/HDL ratio in patients receiving SYNAREL, but there was approximately a 2-fold increase in the LDL/HDL ratio in patients receiving danazol.
Other changes . In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Treatment with SYNAREL was associated with elevations of plasma phosphorus and eosinophil counts, and decreases in serum calcium and WBC counts. Danazol therapy was associated with an increase of hematocrit and WBC.
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 is not absorbed after oral administration.
For the management of endometriosis, the recommended daily dose of SYNAREL 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 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 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; 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.
Sneezing during or immediately after dosing with SYNAREL should be avoided, if possible, since this may impair drug absorption.
At 400 µg/day, a bottle of SYNAREL 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.
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8mL SYNAREL (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.
Store upright at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]. Protect from light.
U.S. Patent No. 4,234,571.
G.D. Searle & Co.
Chicago IL 60680 USA 10/1/99 · A05579