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Synarel®
(nafarelin acetate) Nasal Solution
ENDOMETRIOSIS
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-serylL-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:
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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.
SYNAREL is indicated for treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes.
The diagnosis of central precocious puberty (CPP) is suspected when premature development of secondary sexual characteristics occurs at or before the age of 8 years in girls and 9 years in boys, and is accompanied by significant advancement of bone age and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH. Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical changes associated with increased intracranial pressure. Other causes of sexual precocity, such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other autonomous feminizing or masculinizing disord ers must be excluded by proper clinical hormonal and diagnostic imaging examinations.
For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 μg. The dose can be in creased 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 pa tient'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, tr eatment of CPP with SYNAREL 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; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the d econgestant 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 1600 μg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supp ly to the patient to ensure uninterrupted treatment for the duration of therapy.
Each 0.5 ounce bottle (NDC 0025-0166-08) contains 8 mL 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.
Revised: January 2012. Distributed by: G.D. Searle LLc, Division of Pfizer Inc, NY, NY 10017. Revised: January 2012
In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestiv e 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:
acne (10%)
transient breast enlargement (8%)
vaginal bleeding (8%)
emotional lability (6%)
transient increase in pubic hair (5%)
body odor (4%)
seborrhea (3%)
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 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 is not known.
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
Central/peripheral nervous adverse events: Convulsion.
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 abou t 80% bound to plasma proteins at 4°C, drug interactions would not be expected to occur.
The diagnosis of central precocious puberty (CPP) must be established before treatment is initiated. Regular monitoring of CPP patients is needed to assess both patient response as well as compliance. This is particularly important during the first 6 to 8 weeks of treatment to assure that suppression of pituitary-gonadal function is rapid. Testing may include LH response to GnRH stimulation and circulating gonadal sex steroid levels. Assessment of growth velocity and bone age velocity should begin within 3 to 6 months of treatment initiation.
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 may be increased to 1800 μg/day administered as 600 μg tid.
As with other drugs that stimulate the release of gonadotropins or that induce ovulation, in adult women with endometriosis ovarian cysts have been reported to occur in the firs t two months of therapy with SYNAREL. Many, but not all, of these events occurr ed in women 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/o r surgical intervention. The relevance, if any, of such events in children is unknown.
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 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, ye ast, 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 o n 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 do se-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 breastfed child have not been determined, SYNAREL should not be used by nursing mothers.
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.
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 pharmacoki netics 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 d econgestant 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 n afarelin, 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 documen ted by pregnancies and the effect of long-term use of the drug on fertility is not known.
SYNAREL
(nafarelin acetate) Nasal Spray
Patient Instructions for Use
Introduction
The doctor has prescribed SYNAREL Nasal Solution to treat your child's abnormally early sexual development, which is called central precocious puberty. This pamphlet has two purposes:
Please read this pamphlet carefully. If you still have questions after reading it or if you have questions at any time during your child's treatment with SYNAREL, be sure to check with your child's doctor.
“Central precocious puberty” is called by that name because it is sexual development and growth (puberty) which happens at an abnormally young age (precocious). It is caused by early awakening of a small gland in the brain. Since the brain is part of the “central nervous system,” this early sexual development is called “central.”
In children, SYNAREL is used to relieve the symptoms of central precocious puberty (CPP). CPP is normal puberty that happens at an abnormally young age. In children who are going through puberty (whether it's normal puberty or CPP), a small gland at the base of the brain makes some normal substances that cause the ovaries in girls to make estrogen and progesterone, the female hormones. In boys, it causes the testes to make testosterone, the male hormone. Estrogen and testosterone are the hormones that make girls and boys change into adults. These changes are mainly of 2 kinds: sexual development and a growth spurt. Sexual development includes things like breast and sexual hair growth and menstruation in girls, and growth of sexual organs, sexual hair and facial hair, and voice deepening in boys. The growth spurt during puberty occurs when estrogen (girls) and testosterone (boys) make the long bones of the body grow, so that the child gets taller quickly. When this growth spurt starts at a young age as it does in CPP, children become too tall for their age, but are usually shorter than average as adults.
SYNAREL helps relieve the symptoms of CPP by temporarily preventing the small gland at the base of the brain from making and sending its substances to the ovaries and testes. The ovaries and testes stop producing their hormones as long as SYNAREL is taken regularly, and puberty is interrupted.
Important Information about SYNAREL
Proper Use of SYNAREL for Treatment of Central Precocious Puberty
Preparation of the SYNAREL Nasal Spray unit
For use in your nose only.
Before you use a bottle of SYNAREL nasal spray for the first time, you will need to prime it. This will ensure that you get the right dose of medicine each time you use it.
Important Tips about using SYNAREL
Figure A
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To Prime the Pump:
1. Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure B).
Figure B
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2. Hold the bottle in an upright position away from you. Put two fingers on the “shoulders” of the spray bottle and put your thumb on the bottom of the bottle. Apply pressure evenly to the “shoulders” and push down quickly and firmly 7 to 10 times, until you see a fine spray. Usually you will see the spray after about 7 pumps. (See Figure C).
Figure C
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3. The pump is now primed. Priming only needs to be done 1 time, when you start using a new bottle of SYNAREL. You will waste your medicine if you prime the pump every time you use it and may not have enough medicine for the recommended treatment period.
4. Clean the Spray Tip after Priming:
Figure D
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How to use the SYNAREL Nasal Spray unit for the treatment of Central Precocious Puberty
5. Have your child blow their nose to clear both nostrils before SYNAREL nasal spray is used. If the child is young, you may need to clear the child's nostrils with a bulb syringe (See Figure E).
Figure E
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6. Clean the Spray Tip. Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure F).
Hold the bottle in horizontal position. Rinse the spray tip with warm water while wiping the tip with your finger or soft cloth for 15 seconds. Wipe the spray tip with a soft cloth or tissue to dry.
Do Not try to clean the spray tip using a pointed object.
Do Not try to take apart the pump.
Figure F
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7. The child's head should be bent back a little and the spray tip put into one nostril. The tip should not reach too far into the nose. Aim the spray tip toward the back and outer side of the nose (See Figure G).
Figure G
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8. Close the other nostril with a finger (See Figure H).
Figure H
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9. Apply pressure evenly to the “shoulders” and push down quickly and firmly. Pump the sprayer 1 time, at the same time as the child sniffs in gently. Wait about 30 seconds and apply one more spray in the same nostril. Repeat this process in the other nostril, for a total of four sprays. If the sprayer fails to deliver the dose clean the spray tip (See Step 6 Clean the Spray Tip).
10.Remove the spray tip from the child's nose after all sprays are completed. Keep the child's head tilted backwards for a few seconds. This lets the SYNAREL spray spread over the back of the nose (See Figure I).
Figure I
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11. Clean the Spray Tip after use (See Step 4).
Figure J
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It is important that you clean the spray tip before and after every use. Failure to do this may result in a clogged tip that may cause you to get the wrong dose of medicine.
Important Reminder: Treatment with SYNAREL must be uninterrupted with no missed doses to be effective.
Make sure you use SYNAREL exactly as your doctor tells you to. Make sure to note the date you start each bottle so you do not run out of medicine and miss doses.
Keep out of the reach of children and use carefully as directed.
