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Nafarelin (Systemic)


VA CLASSIFICATION
Primary: HS900

Commonly used brand name(s): Synarel.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Gonadotropin-releasing hormone analog—

gonadotropin inhibitor—

antiendometriotic agent—

Indications

Accepted

Endometriosis (treatment)—Nafarelin is indicated for the management of endometriosis, including treatment of pelvic pain associated with all stages of endometriosis and reduction in the size and number of endometriotic implants {01} {03} {04} {05} {06} {09} {10} {11} {12} {14} {26} {27} {40} {47} {48} {51} {56} {57} {58} {61} {68} {72} {74}. Nafarelin may also have a modest effect on infertility in patients who have moderate endometriosis {01} {03} {04} {05} {06} {11} {23} {26} {27} {47} {57}. Preoperative use of nafarelin in infertile patients with severe endometriosis may also facilitate the surgical procedure {05}.
—Nafarelin has been shown to be as effective as danazol in decreasing the size and extent of endometriotic implants as well as in reducing clinical symptoms of endometriosis {01} {03} {04} {05} {06} {09} {10} {11} {12} {13} {14} {15} {23} {25} {27} {47} {48} {51} {56} {57} {58} {61} {68} {74}.
—Generally, the use of nafarelin or other gonadotropin-releasing hormone (GnRH) analogs for the treatment of endometriosis is limited to short-term, single courses of therapy of 6 months, and to those patients who cannot tolerate the androgenic side effects of danazol or who are not candidates for surgery, because its use is associated with significant, but largely reversible, decreases in bone mass {02} {05} {09} {10} {15} {25} {26} {27} {32} {47} {58} {61} {72}. The long-term clinical significance and safety of these changes on bone mass are unknown {10} {18} {43} {46} {58}.

Puberty, central precocious (treatment)—Nafarelin is indicated for the treatment of central precocious puberty (CPP) in children of both genders. Children suspected of having CPP usually develop secondary sexual characteristics at an earlier stage than cohorts (up to 8 years of age in girls; up to 9 years of age in boys). They also show a significantly advanced bone age that can result in poor adult height attainment. Diagnosis of CPP should be confirmed before initiation of treatment with nafarelin by measuring serum sex steroids and basal gonadotropins levels, testing stimulation response to gonadotropin-releasing hormone (GnRH), assessing diagnostic imaging of the brain (including pituitary and hypothalamus), and performing pelvic ultrasound examination in girls. {61}
—Before beginning treatment for CPP with nafarelin, it is especially important that the patient is willing to comply with dosing and frequent monitoring by the physician during the first 6 to 8 weeks of treatment to assure that suppression of gonadal-pituitary function is rapid. {61}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Nafarelin acetate is a decapeptide, which is an agonistic analog of the hypothalamic hormone, gonadotropin-releasing hormone (GnRH) {05} {09} {10} {13} {20} {26} {51} {58} {61} {62}. Substitution of a naphthylalanine group for glycine at the sixth amino acid position results in higher affinity for the GnRH receptor in the pituitary gland (approximately 200 times greater than GnRH), resistance to degradation by endopeptidases, and increased lipophilicity {05} {09} {10} {13} {19} {20} {26} {51}.
Molecular weight—
    1322.51 (anhydrous free decapeptide) {58}

Mechanism of action/Effect:

Like GnRH, initial or intermittent administration of nafarelin acetate stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes {05} {08} {10} {11} {13} {19} {26} {27} {32} {51} {55} {57} {58} {61}. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor {05} {09} {10} {11} {13} {17} {19} {26} {29} {32} {51} {55} {57} {58} {61}. A reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes occur {05} {09} {10} {11} {13} {17} {19} {26} {29} {32} {55} {62}. This causes a significant and sustained decline in the production of LH and FSH {05} {09} {10} {11} {13} {17} {19} {26} {29} {32} {51} {55} {57} {58} {62}. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes {05} {06} {09} {11} {13} {17} {19} {26} {29} {32} {51} {57} {62}.

Antiendometriotic agent—Like normal endometrium, endometriotic implants contain estrogen receptors {05} {69}. Estrogen stimulates the growth of endometrium {05} {10} {11} {22} {25} {40} {69}. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants {05} {10} {11} {13} {25} {27} {40} {49} {62} {69}. Nafarelin does not abolish the underlying pathophysiology of endometriosis, however {05} {10} {25} {40} {46}. After nafarelin therapy is discontinued, pituitary and ovarian function normalize and estradiol serum concentrations increase to pretreatment levels {05} {10} {25} {40} {46}. Recurrences of endometriosis are frequent after cessation of any hormonal therapy and after surgery that leaves the ovaries and/or uterus intact {05} {10} {25} {40} {46} {57}.

Gonadotropin inhibitor—When used regularly in boys and girls for treatment of central precocious puberty, nafarelin suppresses LH response to gonadotropin-releasing hormone to prepubertal LH levels of less than 15 milli-international units (mIU) within 1 month of treatment. As a result, serum concentrations of the sex steroids estrogen and testosterone decrease. Consequently, secondary sexual development of breasts in 82% of girls and genital development in 100% of boys regresses or ceases; however, pubic hair development, a function of adrenal androgens, regresses in only 54% of boys and girls. Also, linear growth velocity slows to 5 to 6 centimeters (cm) per year or less. Although bone age velocity approaches the normal rate after 1 year of nafarelin treatment, the gap that exists before treatment between bone age and chronological age continues to narrow for 2 to 3 years during nafarelin treatment, improving the chance of attaining the predicted adult height. {61}

Absorption:

Rapidly absorbed across nasal mucosa {51} {52} {58} {61} {73}.

Bioavailability—2.8% (average, relative; range, 1.2 to 5.6%) after a 400-mcg dose {58} {61} {73}.

Protein binding:

78 to 84% (in vitro estimation), primarily to albumin {10} {51} {58} {61}.

Biotransformation:

Enzymatic hydrolysis {51} {52} {58} {61} {73}.

Half-life:

Elimination—3 hours (range, 2 to 4 hours) {51} {58} {61}.

Onset of action:

Within approximately 4 weeks, complete suppression of gonadal steroids occurs {58} {61} {74}.

For treatment of endometriosis—Amenorrhea occurred in 65% of adult patients using 400 mcg of nafarelin a day within 60 days, 80% within 90 days, and 100% within 120 days {61}. After the end of their treatment, 60% of patients were free of symptoms for endometriosis, 32% had mild symptoms, 7% had moderate symptoms, and 1% had severe symptoms {61}. Of the 60% of patients who had complete relief of symptoms, 50% of patients remained symptom-free after 6 months, 33% had mild symptoms, 17% had moderate symptoms, and no patient had severe symptoms {61}.

Time to peak concentration:

10 to 45 minutes {10} {51} {52} {58} {61}.

Peak serum concentration:

200-mcg dose—0.6 nanograms per mL (average) {58} {61}.

400-mcg dose—1.8 to 2.2 nanograms per mL {58} {61}.

600-mcg dose—6.6 nanograms per mL {61}.

Time to peak effect:

Maximal suppression of estradiol serum concentrations—20 days, with use of 400 to 800 mcg per day {27}.

Duration of action:

Relief from symptoms of endometriosis may persist for up to 3 to 6 months after discontinuance of nafarelin therapy {11} {27} {40} {74}.

Elimination:
    In one study in three males given a single subcutaneous dose of radiolabeled nafarelin, 44 to 55% of the radiolabel appeared in urine and 19 to 44% appeared in stool over 7 days following administration {51} {52} {58} {61}. Most of the radioactivity was recovered within the first 48 hours {51} {52} {58} {61}. Approximately 3% appears in the urine unchanged {58} {61}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

In studies conducted in rats and mice, use of nafarelin at proportionately high doses (100 to 500 mcg per kg of body weight [mcg/kg], corresponding to 110 to 560 times the maximum recommended human intranasal dose) and for prolonged periods induced hyperplasia and/or neoplasia of endocrine organs {58} {61}. Increases in pancreatic islet cell adenomas, benign adrenal medullary tumors, Harderian gland tumors, benign testicular and ovarian tumors, pituitary adenomas, and carcinomas were noted in some animal treatment groups {58} {61}. No metastases of these tumors were observed {61}. Generally, tumorigenicity in rodents is particularly sensitive to hormonal stimulation {58} {61}.

No evidence of tumorigenicity has been reported in monkeys or humans {58}.

Mutagenicity

No evidence of mutagenic potential was found in mutagenicity studies conducted in bacterial, yeast, and mammalian systems {58} {61}.

Pregnancy/Reproduction
Fertility—
Nafarelin induces anovulation and amenorrhea in most adult females {15} {40} {44} {49} {50} {51} {58} {61} {74}. This effect is reversible and the average time until the return of menses after discontinuance of therapy is about 45 days {06} {09} {10} {15} {40} {50} {51} {57} {58} {61} {74}. A nonhormonal contraceptive method should be used during nafarelin therapy if conception is likely or possible {57} {58} {61} {69}. If an inadequate dose is used or successive doses are missed, breakthrough bleeding or ovulation may occur {58} {61} {69}.

In one study of adult females using nafarelin for treatment of endometriosis, serum progesterone concentrations indicated that ovulation occurred in less than 18% of menstrual cycles over 3 to 6 months of dosing with 100 or 200 mcg per day {51}. At a dose of 500 mcg twice a day, ovulation was completely suppressed {51}.

Long-term posttreatment follow-up studies of fertility in children treated for central precocious puberty (CPP) have not been done. At 1 year posttreatment, serum sex steroid and gonadotropin levels in girls and boys returned to normal; menses returned in girls and semen analyses were normal in two boys who were examined. {61}

Pregnancy—
Nafarelin should not be given during the course of pregnancy {58} {61}. It is not known what effects nafarelin may have on the embryo if administered during pregnancy {57} {58} {61}. The pre-existence of a pregnancy should be ruled out prior to its use {58} {61}. A nonhormonal contraceptive method should be used during nafarelin therapy {57} {58} {61} {69}.

Major fetal abnormalities were observed in one study in rats, but not in mice or rabbits, after administration of nafarelin throughout gestation {61}. A similar, repeat study in rats failed to show an increase in fetal abnormalities. A dose-related increase in fetal mortality and a decrease in fetal weight occurred in rabbits and rats {61}. The effects on rat fetal mortality were expected results of the changes in gonadal steroid levels induced by nafarelin {61}.

FDA Pregnancy Category X {61}.

Breast-feeding

It is not known whether nafarelin is distributed into breast milk {58} {61}. However, it is recommended that nafarelin not be used by nursing mothers {61}.

Pediatrics

No information is available on the relationship of age to the effects of nafarelin for treatment of endometriosis in patients younger than 18 years of age. Safety and efficacy have not been established. {61}

It is not known if ovarian cysts, a potential side effect that can occur in adult females taking nafarelin for treatment of endometriosis, could also occur in children treated for CPP.

Reversal of the suppressive effects of nafarelin for treatment of CPP in 69 pediatric patients studied 1 year posttreatment has been demonstrated by return of secondary sexual development, menses, and pubertal concentrations of serum gonadotropins and sex steroids. Semen analyses were normal in a few boys after treatment discontinuation; fertility studies in girls have not been done, and nafarelin's potential effect on fertility is not known. {61}


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Decongestants, nasal, topical{57}{58}{61}{72}    (it is not known whether use of topical nasal decongestants will interfere with the absorption of nafarelin {57} {58} {61}; it is recommended that patients allow at least 2 hours {61} to pass after the use of nafarelin before using a topical nasal decongestant {57} {58} {61} {72})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Pituitary gonadotropic function testing and{58}{61}
» Gonadal function testing{58}{61}    (therapeutic doses of nafarelin suppress the pituitary-gonadal system {58} {61}; baseline function is usually restored within 4 to 8 weeks of discontinuance of nafarelin {58} {61})

With physiology/laboratory test values
Alkaline phosphatase, serum and{14}{16}{43}{45}{51}{56}{57}{58}{74}
Calcium-to-creatinine ratio, urine and{06}{10}{15}{16}{32}{43}{44}{54}{57}
Hydroxyproline-to-creatinine ratio, urine and{06}{10}{15}{16}{32}{43}{44}{45}{54}{56}
Phosphate, serum and{43}{44}
Phosphorous, plasma{58}{61}    (values are increased to postmenopausal levels for adults during use of nafarelin, indicating increased bone remodeling {01} {05} {06} {10} {14} {15} {16} {27} {43} {44} {45} {56} {57} {74}; generally reversible within 3 to 6 months of discontinuation of nafarelin therapy {06} {10} {15} {16} {43} {45} {51} {54} {56} {58})


Androstenedione and{28}{29}{32}{41}{42}{48}{50}{51}
» Estradiol and{01}{05}{08}{10}{11}{13}{14}{15}{28}{29}{30}{32}{40}{41}{42}{43}{44}{45}{46}{47}{48}{49}{50}{51}{56}{57}{58}{61}{62}{74}
Follicle-stimulating hormone and{05}{08}{10}{13}{20}{28}{29}{30}{32}{40}{42}{49}{50}{51}{55}{56}{57}{58}{61}{62}
Luteinizing hormone and{05}{08}{10}{13}{20}{28}{29}{30}{32}{40}{41}{42}{49}{50}{51}{55}{57}{58}{61}{62}
» Progesterone and{01}{10}{11}{13}{40}{44}{49}{50}{51}{62}
Sex-hormone binding globulin and{48}{50}
» Testosterone, total and free{28}{29}{32}{41}{42}{48}{51}    (serum concentrations are transiently increased at the onset of therapy {01} {05} {08} {10} {11} {13} {28} {29} {30} {32} {40} {41} {42} {44} {48} {49} {50} {51} {55} {57} {62}; with continued use, serum concentrations will be suppressed {01} {05} {10} {11} {13} {15} {28} {29} {32} {40} {41} {42} {43} {44} {48} {49} {50} {51} {55} {57} {58} {61} {62} {74}. Estradiol serum concentrations will decline to postmenopausal levels {01} {05} {10} {13} {15} {40} {41} {42} {43} {50} {51} {57} {74} in adults. Effects are reversible within 4 to 8 weeks {61} upon discontinuation of nafarelin {01} {05} {11} {13} {15} {28} {29} {40} {41} {42} {43} {50} {55} {58} {61} {74})


» Bone mineral content{01}{05}{06}{10}{11}{13}{15}{25}{27}{32}{39}{43}{45}{46}{50}{51}{58}{61}{69}{71}{72}{74}    (hypoestrogenism-induced loss of bone mineral content occurs in most adult patients during use of nafarelin, which is especially evident in those skeletal regions that are composed mostly of trabecular bone, such as the spinal vertebrae {01} {05} {10} {11} {13} {16} {25} {27} {32} {39} {43} {45} {46} {51} {58} {61} {74}. Bone mineral content decreases reported range from 0 to 2% for the forearm [mostly cortical bone] and from 6 to 11% for the spinal vertebrae, after 6 months of therapy {16} {43} {45} {46} {51} {56} {57}. In the 6 months following discontinuance of therapy, this effect has been reported to be largely reversible, with a net overall loss of approximately one to one and one-half percent {05} {06} {10} {11} {13} {15} {16} {27} {32} {43} {45} {46} {50} {51} {57} {58} {61}. The long-term clinical significance of these changes on bone mass are unknown, and their importance in the selection of therapy is controversial {10} {18} {43} {46} {57})

    (decreased bone density is not seen in children treated with nafarelin for central precocious puberty {78})


Calcium{58}{61}    (serum concentrations are decreased in adults during nafarelin therapy {58} {61})


Eosinophil count{58}    (asymptomatic eosinophilia has occurred in approximately 10 to 15% of adult patients during nafarelin therapy in clinical trials {58})


Triglycerides, serum    (increased above the upper limit of 150 mg per dL in 12% of adult patients in one study {61})


White blood cell count{09}{10}{40}{49}{50}{57}{58}{61}    (asymptomatic leukopenia has occurred in approximately 10 to 15% of adult patients during nafarelin therapy in clinical trials {09} {10} {40} {50} {57} {58} {61})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Uterine bleeding, abnormal, undiagnosed    (may delay diagnosis by masking underlying condition {61})


Risk-benefit should be considered when the following medical problems exist
Allergy to nafarelin acetate{58}{61}
Hypersensitivity to gonadotropin-releasing hormone or agonists or other ingredients in product formulation{61}
Significant risk factors for low bone mineral content{58}{61}{65}{66}    (nafarelin may additionally increase the risk for development of osteopenia or osteoporosis in adult females; repeat courses of gonadotropin-releasing hormone analog therapy for treatment of endometriosis are not advisable {58} {61}. Additional bone loss can occur in adult females using nafarelin for longer than 6 months or when adult females have other known osteoporotic risk factors, such as alcohol and/or tobacco abuse, family history of severe osteoporosis, or long-term use of medications that decrease bone mineral density, including anticonvulsants or corticosteroids {61})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For treatment of CPP
Bone linear growth velocity and bone age velocity determinations and
Imaging studies    (recommended prior to treatment initiation and periodically during treatment, beginning 3 to 6 months after treatment initiation; diagnostic imaging studies should include radiography of the left hand and wrist [or nondominating hand and wrist] for bone age determination, pelvic ultrasonography in females, and magnetic resonance imaging of the brain {53} {78})


Dehydroepiandrosterone concentrations, serum and/or
Estradiol concentrations, serum and/or
Follicle-stimulating hormone concentrations, serum and/or
Human chorionic gonadotropin concentrations, serum and/or
Hydroxyprogesterone concentrations, serum and/or
Luteinizing hormone concentrations, serum and/or
Prolactin concentrations, serum and/or
Testosterone concentrations, serum    (recommended prior to treatment initiation to establish prepubertal gonadotropin response {53}. If gonadal-pituitary function suppression is not apparent within 6 to 8 weeks after therapy with nafarelin is initiated and lack of patient compliance is ruled out, nafarelin should be discontinued and the diagnosis of gonadotropin-independent sexual precocity should be reconsidered. Other possible causes of sexual precocity include adrenal hyperplasia, testoxicosis, and hypothalamic or testicular tumors {61})


Gonadotropin-releasing hormone stimulation test    (recommended prior to treatment initiation to establish prepubertal gonadotropin response {53})


Pregnancy test    (recommended if treatment is not started during menstruation and in patients with irregular menstrual cycles {53})


For treatment of endometriosis
Bone density determination    (recommended if a second course of nafarelin therapy is considered {61})


Pregnancy test    (recommended if treatment is not started during menstruation and in patients with irregular menstrual cycles {61})




Side/Adverse Effects

Note: Some signs of puberty, including uterine bleeding and breast enlargement in girls, are expected and will occur in the first month with use of nafarelin for treatment of central precocious puberty (CPP) until the hypothalamic-pituitary axis becomes suppressed. Suppression usually occurs within 4 weeks. {61}
Relevance of reported pituitary enlargement and asymmetry and pituitary adenoma during nafarelin treatment is not known. In children, regular examinations of the pituitary gland by magnetic resonance imaging (MRI) or computerized axial tomography (CAT) scanning during and after nafarelin treatment showed changes in pituitary shape and size. A pituitary adenoma was discovered in one male child. {61}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
For female patients treated for endometriosis
    
Loss of bone mineral density{61}

Note: Hypoestrogenism-induced loss of bone mineral density may occur in adult females who are using nafarelin for treatment of endometriosis. This loss may not be completely reversible. The risk may be greatest with adult females who use nafarelin for longer than 6 months and for those adult females with additional osteoporotic risk factors, such as alcohol and/or tobacco abuse, family history of severe osteoporosis, and long-term use of medications that decrease bone mineral density, such as anticonvulsants or corticosteroids. {61}


For female patients treated for endometriosis or CPP
    
Breast enlargement —incidence of 8% for patients with CPP{61}
    
changes in uterine bleeding patterns, including breakthrough bleeding {58}{61}(vaginal bleeding between regular menstrual periods), menorrhagia {49}{50}{58}(longer or heavier menstrual periods), spotting {41}{49}{51}{58}{61}(light vaginal bleeding between regular menstrual periods)—may be transient in the treatment of CPP{61}

Note: In the first 2 months after beginning nafarelin therapy, most adult females experience changes in uterine bleeding patterns {58} {61}. However, the continuing occurrence of irregular uterine bleeding may indicate noncompliance with the prescribed therapeutic regimen, the need for an increase in dose {58} {61}, or a pathologic process. Menorrhagia has been reported with low doses (£ 200 mcg per day). {61}


For male or female patients treated for CPP
    
Body odor{61} —incidence of 4%
    
growth of pubic hair{61} —incidence of 5%

Note: Growth of pubic hair may continue throughout treatment with nafarelin since it is caused by adrenal androgens. {61}



Incidence less frequent or rare
For female patients treated for endometriosis and for male or female patients treated for CPP
    
Anaphylaxis or hypersensitivity reaction, immediate (shortness of breath; chest pain; hives)—incidences of 0.2% in the treatment of endometriosis and 2.4% in the treatment of CPP{58}{61}

For female patients treated for endometriosis
    
Arthralgia {09}{58}{61}{77}(joint pain)
    
asthenia {61}(unusual tiredness or weakness)
    
chloasma (patchy brown or dark brown discoloration of skin {61})
    
eye pain {61}
    
galactorrhea {49}{61}{77}(unexpected or excess milk flow from breasts)
    
ovarian cysts
ovarian enlargement
or ovarian hyperstimulation, mild {09}{58}{61}(pelvic bloating or tenderness)
    
palpitations {61}(fast or irregular heartbeat)
    
paresthesia {61}(numbness or tingling of hands or feet)

Note: Ovarian cysts, enlargement, or hyperstimulation have been reported in adult patients using low doses (£ 200 mcg per day) or in the first 2 months of therapy {37} {49} {58} {61}. Ovarian cysts have occurred primarily in adult patients with polycystic ovary disease {58} {61}. Most ovarian cysts resolve spontaneously, within 4 to 6 weeks of initiating therapy, but some cases may require discontinuation of nafarelin and/or surgery {58} {61}.





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
For female patients treated for endometriosis and for male or female patients treated for CPP
    
Acne
    
emotional lability {10}{27}{47}{48}{51}{57}{58}{61}{68}{77}(mood swings)
    
seborrhea (dandruff; oily skin){61}

For female patients treated for endometriosis or CPP
    
Hot flashes —common in adults, occurring transiently in the treatment of CPP{61}

For female patients treated for endometriosis
    
Amenorrhea {06}{09}{11}{14}{15}{27}{28}{29}{39}{40}{42}{43}{44}{50}{51}{61}{62}{74}(stopping of menstrual periods)
    
edema (rapid weight gain; swelling of feet or lower legs)
    
hirsutism (increased hair growth, often abnormally distributed)
    
hypoestrogenism (dyspareunia; reduced breast size; vaginal dryness; oily skin)—occurs in almost all patients{01}{05}{06}{09}{10}{11}{13}{14}{15}{27}{39}{40}{41}{42}{44}{49}{50}{51}{57}{58}{60}{61}{62}{68}{71}{74}{77}
    
increased or decreased libido {61}(increase or decrease in sexual desire)
    
myalgia (muscle pain){61}


Incidence less frequent or rare
For female patients treated for endometriosis and for male or female patients treated for CPP
    
Rhinitis (irritated or runny nose)—incidence of 5 to 10%{09}{10}{11}{18}{20}{41}{49}{51}{58}{61}

For female patients treated for CPP
    
Vaginal discharge {61}(white or brownish vaginal discharge)

For female patients treated for endometriosis
    
Headache, mild and transient{09}{10}{27}{40}{47}{49}{50}{51}{57}{58}{61}{68}{74}
    
maculopapular rash {09}{12}{58}{61}{74}{77}(skin rash)
    
mastalgia {09}{12}{58}{77}(breast pain)
    
mental depression, mild and transient{09}{10}{12}{40}{41}{49}{50}{57}{58}{61}{74}{77}






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nafarelin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to nafarelin acetate or hypersensitivity to gonadotropin-releasing hormone or agonists or other ingredients in product formulation

Pregnancy—Pregnancy should be ruled out prior to use of nafarelin; nonhormonal contraceptive should be used during therapy if conception is likely or possible; stopping medication and alerting physician if pregnancy is suspected





Breast-feeding—Not recommended for use during breast-feeding





Use in children—It is not known if the potential side effect of ovarian cysts that can occur in adult women treated for endometriosis is relevant to children treated for central precocious puberty (CPP); long-term effect on fertility in boys and girls who used nafarelin for treatment of CPP is not known; reversal of nafarelin's suppressive effects and resumption of puberty in pediatric patients has been demonstrated

Other medications, especially topical nasal decongestants; waiting 30 minutes after use of nafarelin to apply nasal decongestant
Other medical conditions, especially significant risk factors for low bone mineral content (for adult females) and uterine bleeding (abnormal and undiagnosed)

Proper use of this medication
Carefully reading patient instruction sheet contained in the package

Proper administration technique

Avoiding sneezing during administration or immediately afterwards to receive the best absorption

Importance of not using more or less medication than amount prescribed

Importance of parents helping children adhere to a regular dosing schedule

» Proper dosing
Missed dose: Using as soon as remembered; not using if not remembered until next day; not doubling doses

» Proper storage

Precautions while using this medication
Importance of regular follow-up visits to monitor progress

For children treated for central precocious puberty
Importance of close monitoring by the physician, during and after nafarelin treatment for central precocious puberty

Telling physician if pubertal symptoms are not suppressed within 6 to 8 weeks, expecting that symptoms may continue or increase for the first few weeks after nafarelin therapy is initiated until medication begins to work

For adult females treated for endometriosis
Possibility of amenorrhea or irregular menstrual periods; checking with physician if regular menstruation does not occur within 60 to 90 days after discontinuation of medication

Advisability of using nonhormonal forms of contraception during therapy

Using a water-based vaginal lubricant if painful sexual intercourse or vaginal dryness is a problem

» Stopping medication and checking with physician if pregnancy is suspected


Side/adverse effects
Signs of potential side effects, especially:

For female patients treated for endometriosis and for male or female patients treated for CPP—Loss of bone mineral density or anaphylaxis or immediate hypersensitivity reaction

For female patients treated for endometriosis or CPP—Breast enlargement or changes in uterine bleeding pattern

For male or female patients treated for CPP—Body odor or growth of pubic hair

For female patients treated for endometriosis—Arthralgia; asthenia; chloasma; eye pain; galactorrhea; ovarian cysts, ovarian enlargement, or ovarian hyperstimulation (mild); palpitations; or paresthesia

Some signs of puberty, including uterine bleeding and breast enlargement in girls, are expected and will occur in the first month of treatment with nafarelin until the hypothalamic-pituitary axis becomes suppressed. Suppression usually occurs within 4 weeks


General Dosing Information
After administration of a dose, the head should be slightly tilted backwards for 30 seconds to allow the medication to reach the back of the nose. Sneezing during or immediately after administering nafarelin may decrease drug absorption and should be avoided when possible. {61}

Diet/Nutrition
Supplementation with calcium has not been shown to help to prevent the loss of bone mineral content associated with the use of GnRH analogs {46}.

For treatment of central precocious puberty
If the patient responds and tolerates nafarelin therapy, treatment should continue until resumption of puberty is desired {61}.

After priming, a nafarelin metered dose inhaler provides 56 sprays or a 7-day supply at a dose of 1600 mcg a day {61}.

For treatment of endometriosis
Information on re-treatment with nafarelin after 6 months of use or use beyond 6 months is not available. If re-treatment with nafarelin is contemplated, bone density should be assessed with respect to the normal range before the second course is initiated. {61}

After priming, a nafarelin metered dose inhaler provides 60 sprays or a 30-day supply at a dose of 400 mcg a day {61}.


Nasal Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of nafarelin base (not the acetate).


NAFARELIN ACETATE NASAL SOLUTION

Usual adult dose
Endometriosis
Intranasal, 200 mcg (base) into one nostril in the morning and 200 mcg into the other nostril in the evening (total daily dose of 400 mcg) for up to six months {01} {05} {06} {09} {10} {11} {12} {14} {16} {39} {45} {46} {47} {48} {51} {56} {57} {58} {61} {74}. Treatment should begin on Days 2 to 4 of the menstrual cycle {01} {10} {48} {51} {56} {58} {61}.

In an occasional patient, a total daily dose of 400 mcg does not produce amenorrhea {58} {61}. If regular menstrual cycles persist after two months of therapy, the total daily dose may be increased to 800 mcg, administered by applying 200 mcg into each nostril in the morning and 200 mcg into each nostril in the evening {01} {05} {11} {39} {47} {57} {58} {61}.


Usual pediatric dose
Endometriosis
Safety and efficacy have not been established for children up to 18 years of age {61}.

Puberty, central precocious
Intranasal, 2 sprays into each nostril (200 mcg [base] each spray) two times a day, morning and evening, giving a total daily dose of 1600 mcg (8 sprays). The dose can be increased to a total daily dose of 1800 mcg (9 sprays), achieved by giving 3 sprays (600 mcg) into alternating nostrils three times a day. {61}


Strength(s) usually available
U.S.—


2 mg (base) per mL (200 mcg per metered spray) (Rx) [Synarel (benzalkonium chloride) (glacial acetic acid) (sodium hydroxide or hydrochloric acid) (sorbitol) (water [purified]){61}]

Canada—


2 mg (base) per mL (200 mcg per metered spray) (Rx) [Synarel (benzalkonium chloride) (glacial acetic acid) (sodium hydroxide or hydrochloric acid) (sorbitol) (water [purified]){58}]

Packaging and storage:
Store bottle upright between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {51} {58} {61}. Protect from light. Protect from freezing. {61}

Auxiliary labeling:
   • For nasal use only.

Note: Dispense manufacturer's patient information {61}.




Revised: 05/27/1998



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