GENERAL PRECAUTIONS SECTION.


General. 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 first two months of therapy with SYNULLREL. Many, but not all, of these events occurred 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/or surgical intervention. The relevance, if any, of such events in children is unknown.

HOW SUPPLIED SECTION.


HOW SUPPLIED. Each 0.5 ounce bottle (NDC 0025-0166-08) contains mL SYNULLREL (nafarelin acetate) Nasal Solution mg/mL (as nafarelin base), and is supplied with metered spray pump that delivers 200 ug of nafarelin per spray. dust cover and leaflet of patient instructions are also included.. Store upright at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from light.

ADVERSE REACTIONS SECTION.


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 weeks of treatment as 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%) [see Warnings] 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 months previously to resume puberty, adrenal rest tumors were found in the left testis. Relationship to SYNULLREL 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 pituitary microadenoma has been suspected in few children. The relationship of these findings to SYNULLREL is not known.. acne (10%). transient breast enlargement (8%) vaginal bleeding (8%) emotional lability (6%) [see Warnings]. transient increase in pubic hair (5%). body odor (4%). seborrhea (3%). Post-Marketing. 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 majority of these cases, pituitary adenoma was diagnosed, with majority of pituitary apoplexy cases occurring within 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.. Psychiatric adverse events: Emotional lability, such as crying, irritability, impatience, anger, and aggression has been observed with GnRH agonists [see Warnings]; Depression, including rare reports of suicidal ideation and attempt, has been reported for GnRH agonists in children treated for central precocious puberty. Many, but not all, of these patients had history of psychiatric illness or other comorbidities with an increased risk of depression.. Central/peripheral nervous adverse events: Convulsion.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 ug/kg/day and mice (18 months) at doses up to 500 ug/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 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 dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was 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 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Nafarelin acetate is 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 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 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 single dose of 400 ug base, the observed peak concentration was 2.2 ng/mL, whereas following single dose of 600 ug base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of 400 ug dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given dose above 600 ug.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 single dose of 200 ug base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following single dose of 400 ug base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from 400 ug dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately hours. About 80% of nafarelin acetate was bound to plasma proteins at 4C. Twice daily intranasal administration of 200 or 400 ug of SYNULLREL 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 SYNULLREL; however, if the use of nasal decongestant for rhinitis is necessary during treatment with SYNULLREL, the decongestant should not be used until at least hours following dosing with SYNULLREL.When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNULLREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within weeks after initiation of therapy. Thereafter, menstruation should cease.In clinical studies the peak response of LH to GnRH stimulation was reduced from pubertal response to 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 to 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 SYNULLREL. 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 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 SYNULLREL 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.

CLINICAL STUDIES SECTION.


Clinical Studies. 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 patients (approximately 0.2%).As would be expected with drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism.In controlled studies comparing SYNULLREL (400 ug/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.. Figure.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in SYNULLREL;2. Undiagnosed abnormal vaginal bleeding;3. Use in pregnancy or in women who may become pregnant while receiving the drug. SYNULLREL may cause fetal harm when administered to pregnant woman. Major fetal abnormalities were observed in rats, but not in mice or rabbits after administration of SYNULLREL during the period of organogenesis. There was dose-related increase in fetal mortality and decrease in fetal weight in rats [see Pregnancy]. The effects on rat fetal mortality are expected consequences of the alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus;4. Use in women who are breast-feeding [see Nursing Mothers].

DESCRIPTION SECTION.


DESCRIPTION. SYNULLREL (nafarelin acetate) Nasal Solution is intended for administration as spray to the nasal mucosa. Nafarelin acetate, the active component of SYNULLREL Nasal Solution, is 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 synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH).Nafarelin acetate has the following chemical structure: CH3COOH H2O (1 2; y 8)SYNULLREL Nasal Solution contains nafarelin acetate (2 mg/mL, content expressed as nafarelin base) in 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 SYNULLREL, each actuation of the unit delivers approximately 100 uL of the spray containing approximately 200 ug nafarelin base. The contents of one spray bottle are intended to deliver at least 60 sprays.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNULLREL is 1600 ug. The dose can be increased to 1800 ug daily if adequate suppression cannot be achieved at 1600 ug/day.The 1600 ug dose is achieved by two sprays (400 ug) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), total of sprays per day. The 1800 ug dose is achieved by sprays (600 ug) into alternating nostrils three times day, total of sprays per day. The patients 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 SYNULLREL 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 SYNULLREL; however, if the use of nasal decongestant for rhinitis is necessary during treatment with SYNULLREL, the decongestant should not be used until at least hours following dosing with SYNULLREL.Sneezing during or immediately after dosing with SYNULLREL should be avoided, if possible, since this may impair drug absorption.At 1600 ug/day, bottle of SYNULLREL provides about 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.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.


Drug/Laboratory Test Interactions. Administration of SYNULLREL in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within to weeks after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to to weeks after discontinuation of therapy with SYNULLREL may be misleading.

DRUG INTERACTIONS SECTION.


Drug Interactions. No pharmacokinetic-based drug-drug interaction studies have been conducted with SYNULLREL. However, because nafarelin acetate is 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 4C, drug interactions would not be expected to occur.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE FOR CENTRAL PRECOCIOUS PUBERTY. (For Endometriosis, See Reverse Side )SYNULLREL 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 years in girls and years in boys, and is accompanied by significant advancement of bone age and/or poor adult height prediction. The diagnosis should be confirmed by pubertal gonadal sex steroid levels and 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 disorders must be excluded by proper clinical hormonal and diagnostic imaging examinations.

INFORMATION FOR PATIENTS SECTION.


Information for Patients, Patients Parents or Guardians. An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information:1. Reversibility of the suppressive effects of nafarelin has been demonstrated by the appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex steroid levels, and/or by 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.2. Patients and their caregivers should be adequately counseled to assure full compliance; irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.3. Inform parents that reports of convulsions have been observed in patients receiving GnRH agonists. Patients with history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk [see Warnings]. 4. Inform caregivers that reports of convulsions have been observed in patients receiving GnRH agonists. Patients with history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk [see Warnings]. 5. During the first month of treatment with SYNULLREL, some signs of puberty, e.g., vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of the drug. Such changes should resolve soon after the first month. lf such resolution does not occur within the first two months of treatment, this may be due to lack of compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are definitively excluded, the dose of SYNULLREL may be increased to 1800 ug/day administered as 600 ug tid.6. Patients with intercurrent rhinitis should consult their physician for the use of topical nasal decongestant. If the use of topical nasal decongestant is required during treatment with SYNULLREL, the decongestant should not be used until at least hours following dosing with SYNULLREL.Sneezing during or immediately after dosing with SYNULLREL should be avoided, if possible, since this may impair drug absorption.

NURSING MOTHERS SECTION.


Nursing Mothers. It is not known whether SYNULLREL is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of SYNULLREL on lactation and/or the breastfed child have not been determined, SYNULLREL should not be used by nursing mothers.

OVERDOSAGE SECTION.


OVERDOSAGE. In experimental animals, single subcutaneous administration of up to 60 times the recommended human dose (on ug/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, SYNULLREL is not absorbed after oral administration.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 8 mL Bottle Label. ALWAYS DISPENSE WITH MEDICATION GUIDEPfizer NDC 0025-0166-08Synarel(R) (nafarelin acetate) nasal solution2 mg/mL (as nafarelin base)SPRAY FOR INTRANULLSAL USE ONLY. Each actuation delivers approximately 200 mcg nafarelin.8 mL (60 metered sprays) Rx only. PRINCIPAL DISPLAY PANEL 8 mL Bottle Label.

PEDIATRIC USE SECTION.


Pediatric Use. Safety and effectiveness of SYNULLREL for endometriosis in patients younger than 18 years have not been established.

PRECAUTIONS SECTION.


PRECAUTIONS. General. 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 first two months of therapy with SYNULLREL. Many, but not all, of these events occurred 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/or surgical intervention. The relevance, if any, of such events in children is unknown.. Information for Patients, Patients Parents or Guardians. An information pamphlet for patients is included with the product. Patients and their caregivers should be aware of the following information:1. Reversibility of the suppressive effects of nafarelin has been demonstrated by the appearance or return of menses, by the return of pubertal gonadotropin and gonadal sex steroid levels, and/or by 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.2. Patients and their caregivers should be adequately counseled to assure full compliance; irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.3. Inform parents that reports of convulsions have been observed in patients receiving GnRH agonists. Patients with history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk [see Warnings]. 4. Inform caregivers that reports of convulsions have been observed in patients receiving GnRH agonists. Patients with history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk [see Warnings]. 5. During the first month of treatment with SYNULLREL, some signs of puberty, e.g., vaginal bleeding or breast enlargement, may occur. This is the expected initial effect of the drug. Such changes should resolve soon after the first month. lf such resolution does not occur within the first two months of treatment, this may be due to lack of compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are definitively excluded, the dose of SYNULLREL may be increased to 1800 ug/day administered as 600 ug tid.6. Patients with intercurrent rhinitis should consult their physician for the use of topical nasal decongestant. If the use of topical nasal decongestant is required during treatment with SYNULLREL, the decongestant should not be used until at least hours following dosing with SYNULLREL.Sneezing during or immediately after dosing with SYNULLREL should be avoided, if possible, since this may impair drug absorption.. Drug Interactions. No pharmacokinetic-based drug-drug interaction studies have been conducted with SYNULLREL. However, because nafarelin acetate is 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 4C, drug interactions would not be expected to occur.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies of nafarelin were conducted in rats (24 months) at doses up to 100 ug/kg/day and mice (18 months) at doses up to 500 ug/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 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 dose-related increase in benign adrenal medullary tumors in treated female rats. In mice, there was 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 months. The effect of treatment of prepubertal rats on the subsequent reproductive performance of mature animals has not been investigated.. Pregnancy. Teratogenic Effects. See Contraindications. Intramuscular SYNULLREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 ug/kg/day (about 0.5, 2, and 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. similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 ug/kg/day and 0.18 ug/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was dose-related increase in fetal mortality and decrease in fetal weight with the highest dose.. Nursing Mothers. It is not known whether SYNULLREL is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of SYNULLREL on lactation and/or the breastfed child have not been determined, SYNULLREL should not be used by nursing mothers.

PREGNULLNCY SECTION.


Pregnancy. Teratogenic Effects. See Contraindications. Intramuscular SYNULLREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 ug/kg/day (about 0.5, 2, and 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. similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 ug/kg/day and 0.18 ug/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was dose-related increase in fetal mortality and decrease in fetal weight with the highest dose.

SPL MEDGUIDE SECTION.


MEDICATION GUIDESYNULLREL (sin-na-rell)(nafarelin acetate) nasal solutionWhat is the most important information should know about SYNULLRELSome people taking GnRH agonists like SYNULLREL have had new or worsened mental (psychiatric) problems. Mental (psychiatric) problems may include emotional symptoms such as:cryingirritabilityrestlessness (impatience)angeracting aggressive Call your childs doctor right away if your child has any new or worsening mental symptoms or problems while taking SYNULLRELSome people taking GnRH agonists like SYNULLREL have had seizures. The risk of seizures may be higher in people who:have history of seizures.have history of epilepsy. have history of brain or brain vessel (cerebrovascular) problems or tumors. are taking medicine that has been connected to seizures such as taking bupropion or selective serotonin reuptake inhibitors (SSRIs). Seizures have also happened in people who have not had any of these problems.Call your childs doctor right away if your child has seizure while taking SYNULLREL.What is SYNULLREL SYNULLREL is gonadotropin releasing hormone (GnRH) medicine used for the treatment of children with central precocious puberty (CPP). Do not give SYNULLREL if your child:is allergic to gonadotropin releasing hormone (GnRH), GnRH agonist medicines, or any of the ingredients in SYNULLREL. See the end of this Medication Guide for complete list of ingredients in SYNULLREL.has unusual vaginal bleeding that has not been checked by her doctor.is pregnant or may become pregnant. SYNULLREL can cause birth defects or loss of the baby. If your child becomes pregnant call your doctor.is breastfeeding or plans to breastfeed. It is not known if SYNULLREL passes into breast milk. You and your childs doctor should decide if your child will take SYNULLREL or breastfeed. Do not breastfeed while taking SYNULLREL. Before your child takes SYNULLREL, tell your doctor about all of your childs medical conditions, including if they:have history of mental (psychiatric) problems. have or have had history of seizures.have history of epilepsy.have history of brain or brain vessel (cerebrovascular) problems or tumors are taking medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs).Tell your doctor about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should your child take SYNULLRELYour childs doctor should do tests to make sure your child has CPP before treating your child with SYNULLREL.Keep all scheduled visits to the doctor. If scheduled doses are missed, your child may start having signs of puberty again. The doctor will do regular exams and blood tests to check for signs of puberty. Take SYNULLREL exactly as your doctor tells you to take it. See detailed Instructions for Use at the end of this Medication Guide for information about the right way to use SYNULLREL. Your childs doctor will tell you how much SYNULLREL your child is to take and when to take it. If your doctor increases your childs daily dose of SYNULLREL, bottle will not last the standard days. Talk with your childs doctor to make sure your child has enough SYNULLREL to take their prescribed dose every day.What should your child avoid while taking SYNULLRELYour child should avoid sneezing while taking SYNULLREL or right after using it, if possible. This could reduce the amount of medicine your childs body absorbs. If your child needs to use nasal decongestant spray while being treated with SYNULLREL, they should not use the decongestant spray for at least hours after taking the dose of SYNULLREL. What are the possible side effects of SYNULLRELSYNULLREL may cause serious side effects, including: See What is the most important information should know about SYNULLREL in the first month of treatment, SYNULLREL can cause an increase in some hormones. During this time you may notice more signs of puberty in your child, including vaginal bleeding and breast enlargement in girls. Within month of treatment, you should see signs in your child that puberty is stopping.The side effects of SYNULLREL include:allergic reactions such as shortness of breath, chest pain, hives, rash, and itchingacnetemporary increase in pubic hairbody odorflaky, scaly skinhot flashesstuffy or runny nose (rhinitis)white or brown vaginal dischargeThese are not all of the possible side effects of SYNULLREL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General Information about the safe and effective use of SYNULLREL.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use SYNULLREL for condition for which it is not prescribed. Do not give SYNULLREL to other people, even if they have the same symptoms that you have. It may harm them.You can ask your doctor or pharmacist for information about SYNULLREL that is written for health professionals.What are the ingredients in SYNULLRELActive ingredient: nafarelin acetate Inactive ingredients: benzalkonium chloride, glacial acetic acid, sodium hydroxide or hydrochloric acid (to adjust pH), sorbitol, and purified water Some people taking GnRH agonists like SYNULLREL have had new or worsened mental (psychiatric) problems. Mental (psychiatric) problems may include emotional symptoms such as:cryingirritabilityrestlessness (impatience)angeracting aggressive crying. irritability. restlessness (impatience). anger. acting aggressive. Some people taking GnRH agonists like SYNULLREL have had seizures. The risk of seizures may be higher in people who:have history of seizures.have history of epilepsy. have history of brain or brain vessel (cerebrovascular) problems or tumors. are taking medicine that has been connected to seizures such as taking bupropion or selective serotonin reuptake inhibitors (SSRIs). have history of seizures.. have history of epilepsy. have history of brain or brain vessel (cerebrovascular) problems or tumors. are taking medicine that has been connected to seizures such as taking bupropion or selective serotonin reuptake inhibitors (SSRIs).. is allergic to gonadotropin releasing hormone (GnRH), GnRH agonist medicines, or any of the ingredients in SYNULLREL. See the end of this Medication Guide for complete list of ingredients in SYNULLREL.. has unusual vaginal bleeding that has not been checked by her doctor.. is pregnant or may become pregnant. SYNULLREL can cause birth defects or loss of the baby. If your child becomes pregnant call your doctor.. is breastfeeding or plans to breastfeed. It is not known if SYNULLREL passes into breast milk. You and your childs doctor should decide if your child will take SYNULLREL or breastfeed. Do not breastfeed while taking SYNULLREL. have history of mental (psychiatric) problems. have or have had history of seizures.. have history of epilepsy.. have history of brain or brain vessel (cerebrovascular) problems or tumors are taking medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs).. Your childs doctor should do tests to make sure your child has CPP before treating your child with SYNULLREL.. Keep all scheduled visits to the doctor. If scheduled doses are missed, your child may start having signs of puberty again. The doctor will do regular exams and blood tests to check for signs of puberty. Take SYNULLREL exactly as your doctor tells you to take it. See detailed Instructions for Use at the end of this Medication Guide for information about the right way to use SYNULLREL. Your childs doctor will tell you how much SYNULLREL your child is to take and when to take it. If your doctor increases your childs daily dose of SYNULLREL, bottle will not last the standard days. Talk with your childs doctor to make sure your child has enough SYNULLREL to take their prescribed dose every day.. Your child should avoid sneezing while taking SYNULLREL or right after using it, if possible. This could reduce the amount of medicine your childs body absorbs. If your child needs to use nasal decongestant spray while being treated with SYNULLREL, they should not use the decongestant spray for at least hours after taking the dose of SYNULLREL. See What is the most important information should know about SYNULLREL in the first month of treatment, SYNULLREL can cause an increase in some hormones. During this time you may notice more signs of puberty in your child, including vaginal bleeding and breast enlargement in girls. Within month of treatment, you should see signs in your child that puberty is stopping.. allergic reactions such as shortness of breath, chest pain, hives, rash, and itching. acne. temporary increase in pubic hair. body odor. flaky, scaly skin. hot flashes. stuffy or runny nose (rhinitis). white or brown vaginal discharge.

SPL PATIENT PACKAGE INSERT SECTION.


SYNULLRELnafarelin acetateNasal SprayPatient Instructions for UseIntroductionYour doctor has prescribed SYNULLREL Nasal Solution to treat your symptoms of endometriosis. This pamphlet has two purposes:1.)to review information your doctor has given you about SYNULLREL; and2.)to give you information about how to use SYNULLREL properly.Please read this pamphlet carefully. If you still have questions after reading it or if you have questions at any time during your treatment with SYNULLREL, be sure to check with your doctor.SYNULLREL is used to relieve the symptoms of endometriosis. The lining of the uterus is called the endometrium, and part of it is shed during menses. In endometriosis, endometrial tissue is also found outside the uterus and, like normal endometrial tissue, can bleed during menstrual cycle. It is, in part, this monthly activity that causes you to have symptoms during your cycle. Most often, this out-of-place endometrial tissue is found around the uterus, ovaries, the intestine or other organs in the pelvis. Although some women with endometriosis have no symptoms, many have problems such as severe menstrual cramps, pain during sexual intercourse, low back pain, and painful bowel movements.Endometrial tissue is affected by the bodys hormones, especially estrogen, which is made by the ovaries. When estrogen levels are low, endometrial tissue shrinks (perhaps even disappears), and symptoms of endometriosis ease. SYNULLREL temporarily reduces estrogen in the body and temporarily relieves the symptoms of endometriosis.Important Information about SYNULLRELYou should not use SYNULLREL ifyou are pregnant.you are breast feeding.you have abnormal vaginal bleeding that has not been checked into by your doctor.you are allergic to any of the ingredients of SYNULLREL (nafarelin acetate, benzalkonium chloride, acetic acid, sodium hydroxide, hydrochloric acid, sorbitol, purified water). SYNULLREL is prescription medicine that should be used according to your doctors directions. SYNULLREL comes as special nasal spray that gives measured amount of medicine. To be effective, SYNULLREL must be used every day, twice day, for the whole treatment period.It is important to use non-hormonal method of contraception (such as diaphragm with contraceptive jelly, IUD, condoms) while taking SYNULLREL. You should not use birth control pills while taking SYNULLREL.If you miss or more doses of SYNULLREL, vaginal bleeding (often called breakthrough bleeding) may occur. If you miss successive doses of SYNULLREL and have not been using contraception as described above, release of an egg from the ovary (ovulation) may occur, with the possibility of pregnancy. Under these circumstances you must see your physician to make sure you are not pregnant. If you should become pregnant while using SYNULLREL, you must discuss the possible risks to the fetus and the choices available to you with your physician.Because SYNULLREL works by temporarily reducing the bodys production of estrogen, female hormone produced by the ovary, you may have some of the same changes that normally occur at the time of menopause, when the bodys production of estrogen naturally decreases. For the first two months after you start using SYNULLREL, you may experience some irregular vaginal spotting or bleeding. The duration and intensity of this bleeding may vary; it may be similar to your usual menstruation, or it may be lighter or heavier. The duration may also vary from brief to prolonged. In any case, you can expect this bleeding to stop by itself. After the first two months of treatment with SYNULLREL, you can expect decrease in menstrual flow, and your periods may stop altogether. However, if you miss one or more doses of SYNULLREL, you may continue to experience vaginal bleeding. If you continue to experience normal menstrual cycles after two months use of SYNULLREL, you should see your doctor about the continued periods. Other changes due to decreased estrogen include hot flashes, vaginal dryness, headaches, mood changes, and decreased interest in sex. Most of these changes are caused by low estrogen levels and may occur during treatment with SYNULLREL. Some patients may also experience acne, muscle pain, reduced breast size, and irritation of the tissues inside the nose. These symptoms should disappear after you stop taking the drug.When you take SYNULLREL, your estrogen levels will be low. Low estrogen levels can result in small loss of mineral from bone, some of which may not be reversible. During one six-month treatment period, this small loss of mineral from bone should not be important.There are certain conditions that may increase the possibility of the thinning of your bones when you take drug such as SYNULLREL. They are:excessive use of alcohol;smoking;family history of osteoporosis (thinning of the bones with fractures);taking other medications that can cause thinning of the bones.You should discuss the possibility of osteoporosis or thinning of the bones with your physician before starting SYNULLREL. You should also be aware that repeat treatments are not recommended since they may put you at greater risk of bone thinning, particularly if you have the above conditions.During studies, menstruation usually resumed within to months of stopping treatment with SYNULLREL. At the end of treatment 60% of patients treated with SYNULLREL 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 at the end of the six month post-treatment period; 33% had mild symptoms; 50% were symptom free; no patient had severe symptoms.Retreatment cannot be recommended since the safety of such retreatment is not known.It is all right to use nasal decongestant spray while you are being treated with SYNULLREL if you follow these simple rules. Use SYNULLREL first. Wait at least hours after using SYNULLREL before you use the decongestant spray.You should avoid sneezing during or immediately after using SYNULLREL, if possible, since sneezing may impair drug absorption.Proper use of SYNULLREL for Treatment of EndometriosisWhen you start to use SYNULLREL, the first dose should be taken between the second and fourth day after the beginning of your menstrual bleeding. You should continue taking SYNULLREL every day as prescribed. Do not miss single dose. Unless your doctor has given you special instructions, follow the steps for using SYNULLREL twice each day, about 12 hours between doses:once in the morning in one nostril (for example, a.m.)once in the evening in the other nostril (for example, p.m.)The length of treatment is usually about months, unless your doctor has given you special instructions.Because it is so important that you do not miss single dose of SYNULLREL, here are some suggestions to help you remember:Keep your SYNULLREL in place where you will be reminded to use it each morning and each evening -- next to your toothbrush is one possibility.Keep track of each dose on calendar.Make note on your calendar on the day you start new bottle of SYNULLREL. You can also mark the date you started right on the bottle. Be sure to refill your prescription before the 30 days are up so you will have new bottle on hand. bottle of SYNULLREL should not be used for longer than 30 days (60 sprays). Each bottle contains sufficient quantity of nasal solution for initial priming of the pump and 30 days (60 sprays) of treatment. At the end of 30 days, small amount of liquid will be left in the bottle. Do not try to use up that leftover amount because you might get too low dose, which could interfere with the effectiveness of your treatment. Dispose of the bottle and do not reuse.If your doctor increases your daily dose of SYNULLREL, then your bottle will not last the standard 30 days. Please discuss this with your doctor to be sure that you have an adequate supply for uninterrupted treatment with SYNULLREL to complete the recommended treatment period.Preparation of the SYNULLREL Nasal Spray unitFor use in your nose only.Before you use SYNULLREL 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 SYNULLRELYour pump should produce fine mist, which can only happen by quick and firm pumping action. It is normal to see some larger droplets of liquid within the fine mist. However, if SYNULLREL comes out of the pump as thin stream of liquid instead of fine mist, SYNULLREL may not work as well, and you should talk to your pharmacist.Be sure to clean the Spray Tip before and after every use. (See Step 4). Failure to do this may result in clogged tip that may cause you not to get the right amount of medicine that is prescribed for you. The pump is made to deliver only set amount of medicine, no matter how hard you pump it.Do Not try to make the tiny hole in the spray tip larger. If the hole is made larger the pump will deliver wrong dose of SYNULLREL.Figure ATo Prime the Pump:Figure 1.Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure B).Figure 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 to 10 times, until you see fine spray. Usually you will see the spray after about pumps. (See Figure C).3.The pump is now primed. Priming only needs to be done time, when you start using new bottle of SYNULLREL. You will waste your medicine if you prime the pump every time you use it and may not have enough medicine for 30 days of treatment.Figure 4.Clean the Spray Tip after Priming: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 soft cloth or tissue to dry.Replace the white safety clip and the clear plastic dust cover on the spray bottle (See Figure D).Do Not try to clean the spray tip using pointed object. Do Not take apart the pump.How to use the SYNULLREL Nasal Spray unit for the treatment of EndometriosisFigure 5.Gently blow your nose to clear both nostrils before you use SYNULLREL nasal spray (See Figure E).Figure 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 soft cloth or tissue to dry.Do Not try to clean the spray tip using pointed object.Do Not try to take apart the pump. Figure G7.Bend your head forward and put the spray tip into one nostril. The tip should not reach too far into your nose. Aim the spray tip toward the back and outer side of your nose (See Figure G).Figure 8.Close the other nostril with your finger (See Figure H).9.Apply pressure evenly to the shoulders and push down quickly and firmly. Pump the sprayer time, at the same time as you sniff in gently. If the sprayer fails to deliver the dose clean the spray tip (See Step Clean the Spray Tip).Figure 10.Remove the spray tip from your nose and tilt your head backwards for few seconds. This lets the SYNULLREL spray spread over the back of your nose (See Figure I).Do not spray in your other nostril unless your doctor has instructed you to do so.Figure 11.Clean the Spray Tip after use (See Step 4).It is important that you clean the spray tip before and after every use. Failure to do this may result in clogged tip that may cause you to get the wrong dose of medicine.Important Reminder: Treatment with SYNULLREL must be uninterrupted with no missed doses to be effective.Make sure you use SYNULLREL exactly as your doctor tells you. 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.Storage Instructions:Store SYNULLREL at 59F to 86F (15C to 30C). Store the SYNULLREL bottle upright.Keep SYNULLREL out of the light.Do not freeze SYNULLREL.This products label may have been updated. For current full prescribing information, please visit www.pfizer.com.LAB-0278-7.0Revised: December 2020. 1.)to review information your doctor has given you about SYNULLREL; and. 2.)to give you information about how to use SYNULLREL properly.. You should not use SYNULLREL ifyou are pregnant.you are breast feeding.you have abnormal vaginal bleeding that has not been checked into by your doctor.you are allergic to any of the ingredients of SYNULLREL (nafarelin acetate, benzalkonium chloride, acetic acid, sodium hydroxide, hydrochloric acid, sorbitol, purified water). you are pregnant.. you are breast feeding.. you have abnormal vaginal bleeding that has not been checked into by your doctor.. you are allergic to any of the ingredients of SYNULLREL (nafarelin acetate, benzalkonium chloride, acetic acid, sodium hydroxide, hydrochloric acid, sorbitol, purified water).. SYNULLREL is prescription medicine that should be used according to your doctors directions. SYNULLREL comes as special nasal spray that gives measured amount of medicine. To be effective, SYNULLREL must be used every day, twice day, for the whole treatment period.. It is important to use non-hormonal method of contraception (such as diaphragm with contraceptive jelly, IUD, condoms) while taking SYNULLREL. You should not use birth control pills while taking SYNULLREL.. If you miss or more doses of SYNULLREL, vaginal bleeding (often called breakthrough bleeding) may occur. If you miss successive doses of SYNULLREL and have not been using contraception as described above, release of an egg from the ovary (ovulation) may occur, with the possibility of pregnancy. Under these circumstances you must see your physician to make sure you are not pregnant. If you should become pregnant while using SYNULLREL, you must discuss the possible risks to the fetus and the choices available to you with your physician.. Because SYNULLREL works by temporarily reducing the bodys production of estrogen, female hormone produced by the ovary, you may have some of the same changes that normally occur at the time of menopause, when the bodys production of estrogen naturally decreases. For the first two months after you start using SYNULLREL, you may experience some irregular vaginal spotting or bleeding. The duration and intensity of this bleeding may vary; it may be similar to your usual menstruation, or it may be lighter or heavier. The duration may also vary from brief to prolonged. In any case, you can expect this bleeding to stop by itself. After the first two months of treatment with SYNULLREL, you can expect decrease in menstrual flow, and your periods may stop altogether. However, if you miss one or more doses of SYNULLREL, you may continue to experience vaginal bleeding. If you continue to experience normal menstrual cycles after two months use of SYNULLREL, you should see your doctor about the continued periods. Other changes due to decreased estrogen include hot flashes, vaginal dryness, headaches, mood changes, and decreased interest in sex. Most of these changes are caused by low estrogen levels and may occur during treatment with SYNULLREL. Some patients may also experience acne, muscle pain, reduced breast size, and irritation of the tissues inside the nose. These symptoms should disappear after you stop taking the drug.. When you take SYNULLREL, your estrogen levels will be low. Low estrogen levels can result in small loss of mineral from bone, some of which may not be reversible. During one six-month treatment period, this small loss of mineral from bone should not be important.There are certain conditions that may increase the possibility of the thinning of your bones when you take drug such as SYNULLREL. They are:excessive use of alcohol;smoking;family history of osteoporosis (thinning of the bones with fractures);taking other medications that can cause thinning of the bones.You should discuss the possibility of osteoporosis or thinning of the bones with your physician before starting SYNULLREL. You should also be aware that repeat treatments are not recommended since they may put you at greater risk of bone thinning, particularly if you have the above conditions.. excessive use of alcohol;. smoking;. family history of osteoporosis (thinning of the bones with fractures);. taking other medications that can cause thinning of the bones.. During studies, menstruation usually resumed within to months of stopping treatment with SYNULLREL. At the end of treatment 60% of patients treated with SYNULLREL 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 at the end of the six month post-treatment period; 33% had mild symptoms; 50% were symptom free; no patient had severe symptoms.. Retreatment cannot be recommended since the safety of such retreatment is not known.. It is all right to use nasal decongestant spray while you are being treated with SYNULLREL if you follow these simple rules. Use SYNULLREL first. Wait at least hours after using SYNULLREL before you use the decongestant spray.. You should avoid sneezing during or immediately after using SYNULLREL, if possible, since sneezing may impair drug absorption.. When you start to use SYNULLREL, the first dose should be taken between the second and fourth day after the beginning of your menstrual bleeding. You should continue taking SYNULLREL every day as prescribed. Do not miss single dose. Unless your doctor has given you special instructions, follow the steps for using SYNULLREL twice each day, about 12 hours between doses:once in the morning in one nostril (for example, a.m.)once in the evening in the other nostril (for example, p.m.)The length of treatment is usually about months, unless your doctor has given you special instructions.. once in the morning in one nostril (for example, a.m.). once in the evening in the other nostril (for example, p.m.). Because it is so important that you do not miss single dose of SYNULLREL, here are some suggestions to help you remember:Keep your SYNULLREL in place where you will be reminded to use it each morning and each evening -- next to your toothbrush is one possibility.Keep track of each dose on calendar.Make note on your calendar on the day you start new bottle of SYNULLREL. You can also mark the date you started right on the bottle. Be sure to refill your prescription before the 30 days are up so you will have new bottle on hand. Keep your SYNULLREL in place where you will be reminded to use it each morning and each evening -- next to your toothbrush is one possibility.. Keep track of each dose on calendar.. Make note on your calendar on the day you start new bottle of SYNULLREL. You can also mark the date you started right on the bottle. Be sure to refill your prescription before the 30 days are up so you will have new bottle on hand.. bottle of SYNULLREL should not be used for longer than 30 days (60 sprays). Each bottle contains sufficient quantity of nasal solution for initial priming of the pump and 30 days (60 sprays) of treatment. At the end of 30 days, small amount of liquid will be left in the bottle. Do not try to use up that leftover amount because you might get too low dose, which could interfere with the effectiveness of your treatment. Dispose of the bottle and do not reuse.. If your doctor increases your daily dose of SYNULLREL, then your bottle will not last the standard 30 days. Please discuss this with your doctor to be sure that you have an adequate supply for uninterrupted treatment with SYNULLREL to complete the recommended treatment period.. Your pump should produce fine mist, which can only happen by quick and firm pumping action. It is normal to see some larger droplets of liquid within the fine mist. However, if SYNULLREL comes out of the pump as thin stream of liquid instead of fine mist, SYNULLREL may not work as well, and you should talk to your pharmacist.. Be sure to clean the Spray Tip before and after every use. (See Step 4). Failure to do this may result in clogged tip that may cause you not to get the right amount of medicine that is prescribed for you. The pump is made to deliver only set amount of medicine, no matter how hard you pump it.. Do Not try to make the tiny hole in the spray tip larger. If the hole is made larger the pump will deliver wrong dose of SYNULLREL.. 1.Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure B).. 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 to 10 times, until you see fine spray. Usually you will see the spray after about pumps. (See Figure C).. 3.The pump is now primed. Priming only needs to be done time, when you start using new bottle of SYNULLREL. You will waste your medicine if you prime the pump every time you use it and may not have enough medicine for 30 days of treatment.. 4.Clean the Spray Tip after Priming: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 soft cloth or tissue to dry.Replace the white safety clip and the clear plastic dust cover on the spray bottle (See Figure D).Do Not try to clean the spray tip using pointed object. Do Not take apart the pump.. 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 soft cloth or tissue to dry.. Replace the white safety clip and the clear plastic dust cover on the spray bottle (See Figure D).. Do Not try to clean the spray tip using pointed object. Do Not take apart the pump.. 5.Gently blow your nose to clear both nostrils before you use SYNULLREL nasal spray (See Figure E).. 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 soft cloth or tissue to dry.Do Not try to clean the spray tip using pointed object.Do Not try to take apart the pump. 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 soft cloth or tissue to dry.. Do Not try to clean the spray tip using pointed object.. Do Not try to take apart the pump.. 7.Bend your head forward and put the spray tip into one nostril. The tip should not reach too far into your nose. Aim the spray tip toward the back and outer side of your nose (See Figure G).. 8.Close the other nostril with your finger (See Figure H).. 9.Apply pressure evenly to the shoulders and push down quickly and firmly. Pump the sprayer time, at the same time as you sniff in gently. If the sprayer fails to deliver the dose clean the spray tip (See Step Clean the Spray Tip).. 10.Remove the spray tip from your nose and tilt your head backwards for few seconds. This lets the SYNULLREL spray spread over the back of your nose (See Figure I).Do not spray in your other nostril unless your doctor has instructed you to do so.. 11.Clean the Spray Tip after use (See Step 4).. Store SYNULLREL at 59F to 86F (15C to 30C). Store the SYNULLREL bottle upright.. Keep SYNULLREL out of the light.. Do not freeze SYNULLREL.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Logo.

SPL UNCLASSIFIED SECTION.


CENTRAL PRECOCIOUS PUBERTY (FOR ENDOMETRIOSIS, SEE REVERSE SIDE)PHYSICIAN LABELING.

STORAGE AND HANDLING SECTION.


Store upright at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from light.

TERATOGENIC EFFECTS SECTION.


Teratogenic Effects. See Contraindications. Intramuscular SYNULLREL was administered to rats during the period of organogenesis at 0.4, 1.6, and 6.4 ug/kg/day (about 0.5, 2, and 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. similar, repeat study at the same doses in rats and studies in mice and rabbits at doses up to 600 ug/kg/day and 0.18 ug/kg/day, respectively, failed to demonstrate an increase in fetal abnormalities after administration during the period of organogenesis. In rats and rabbits, there was dose-related increase in fetal mortality and decrease in fetal weight with the highest dose.

WARNINGS SECTION.


WARNINGS. 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 to 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 to 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 SYNULLREL may be increased to 1800 ug/day administered as 600 ug tid.Psychiatric events have been reported in patients taking GnRH agonists. Postmarketing reports with this class of drugs includes symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with SYNULLREL. Post-marketing reports of convulsions have been observed in patients receiving GnRH agonists. These have included patients with history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.