Nafarelin

INDICATIONS AND USAGE FOR CENTRAL PRECOCIOUS PUBERTY (For Endometriosis, See Reverse Side ) 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 disorders must be excluded by proper clinical hormonal and diagnostic imaging examinations.

DOSAGE AND ADMINISTRATION For the treatment of central precocious puberty (CPP), the recommended daily dose of SYNAREL is 1600 µg. The dose can be increased to 1800 µg daily if adequate suppression cannot be achieved at 1600 µg/day. The 1600 µg dose is achieved by two sprays (400 µg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 µg dose is achieved by 3 sprays (600 µg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. If the prescribed therapy has been well tolerated by the patient, treatment of CPP with SYNAREL 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 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 1600 µg/day, a bottle of SYNAREL provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy.

ADVERSE REACTIONS In clinical trials of 155 pediatric patients, 2.6% reported symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash, and pruritus. In these 155 patients treated for an average of 41 months and as long as 80 months (6.7 years), adverse events most frequently reported (>3% of patients) consisted largely of episodes occurring during the first 6 weeks of treatment as a result of the transient stimulatory action of nafarelin upon the pituitary-gonadal axis: 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 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. 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 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. 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 a history of psychiatric illness or other comorbidities with an increased risk of depression. Central/peripheral nervous adverse events: Convulsion, pseudotumor cerebri (idiopathic intracranial hypertension).

Drug Interactions 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.