Nafarelin acetate is an intranasally administered synthetic analog of endogenous gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH). Substitution of one amino acid normally found in GnRH leads to sustained activity of this drug that aids in hormonal control; in addition, nafarelin is approximately 200 times more potent than endogenous GnRH. Nafarelin is used in the treatment of children with central precocious puberty (CPP). Nafarelin is also used for hormone-sensitive conditions in women including endometriosis, uterine leiomyomata (fibroids), and hirsutism. The maximum length of therapy for these indications in women is 6 months to minimize the risk of bone mineral density loss. Nafarelin is also used for pituitary down-regulation prior to controlled ovarian hyperstimulation and subsequent in vitro fertilization. Nafarelin has been used subcutaneously in men with benign prostatic hyperplasia (BPH) to shrink prostatic tissue; however, the subcutaneous formulation of nafarelin is not available in the US. The manufacturer reports that for the treatment of symptoms associated with endometriosis, intranasal nafarelin at a dose of 400 mcg/day is clinically comparable to monthly IM injections of leuprolide depot 3.75 mg. However, in one study, nafarelin use in women with severe symptoms of endometriosis was associated with less bone mineral density loss and fewer days with hypoestrogenic symptoms (including hot flashes) when compared to leuprolide; consequently, nafarelin was associated with a greater improvement in quality of life. Intranasal nafarelin (Synarel(R)) was approved by the FDA in February of 1990 and is FDA-approved for the treatment of CPP in children and endometriosis in female patients >= 18 years of age.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Inhalation Administration
Intranasal Inhalation Administration
-NOTE: Each spray of nafarelin nasal solution delivers 200 mcg/spray.
-Patients should be instructed on the proper use of nafarelin nasal solution, including strict compliance with the dosage regimen.
-Before using for the first time, the unit must be primed. Keeping the sprayer pointed away from the patient, other people, and pets, pump the activator 7-10 times until a fine mist appears. The inhaler only needs to be primed prior to the first use of a new bottle.
-Patients should be instructed to tilt their head forward during administration of the dose. Once the dose has been delivered, the patient should tilt their head backwards to ensure appropriate dose delivery.
-If sneezing occurs during administration, repeat dosing may be advisable; sneezing may impair absorption.
-To avoid improper dose delivery due to a clogged tip, the spray tip should be cleaned after each dose. The spray tip should be rinsed with warm water while wiping tip with a finger or soft cloth for 15 seconds. Dry the tip with a soft cloth or tissue.
-To avoid the spread of infection, do not use the sprayer in more than one person.
Regular examination of the pituitary gland by magnetic resonance imaging (MRI) or computed assisted tomography (CT) of children during long term treatment with nafarelin therapy as well as during post-treatment 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 microadenomas have been suspected in a few children. The relationship of these findings to nafarelin is unknown. Furthermore, in one male patient with concomitant congenital adrenal hyperplasia who had discontinued nafarelin therapy 8 months previously to resume puberty, adrenal rest tumors were found in the left testes. The relationship to nafarelin is unlikely.
Many adverse effects of nafarelin are directly related to alterations in sex hormones and include hot flashes (90% in adult women, 3% in children), acne vulgaris (13% in adult women, 10% in children), and seborrhea (8% in adult women, 3% in children). In children treated for precocious puberty, breast enlargement (8%), vaginal bleeding (8%), transient increase in pubic hair (5%), drug-induced body odor (4%), and vaginal discharge (3%) were reported. In children, some signs of puberty may occur with nafarelin initiation and is an expected initial effect due to the transient stimulatory action of nafarelin upon the pituitary-gonadal axis. If resolution of the effects do not occur within the first two months of treatment, assess patient compliance and determine the presence of gonadotropin independent sexual precocity. In women treated with nafarelin for endometriosis, libido decrease (21%), vaginal dryness (19%), breast size reduction (10%), breast engorgement (less than 1%), lactation (less than 1%), cholasma (less than 1%), edema (8%), weight gain (8%), hirsutism (3%), libido increase (1%), and menstrual irregularity were reported and are largely due to hypoestrogenism. Weight loss was reported in less than 5% of adult females receiving nafarelin. In female patients, amenorrhea occurs with effective doses of nafarelin; patients should notify their prescriber or health care professional if regular menstruation continues. Patients missing one or more successive doses of nafarelin may experience breakthrough bleeding. Some patients may have delayed return of menses once nafarelin therapy is stopped; however, rarely do patients experience persistent amenorrhea.
Hypersensitivity reactions including dyspnea, chest pain (unspecified), urticaria, rash (unspecified), and pruritus occurred in 0.2% of 1,509 adult females and in 2.6% of 155 children during clinical trials of nafarelin. Maculopapular rash was noted in less than 1% of adult women who received nafarelin.
In clinical trials with nafarelin, adverse central nervous system (CNS) reactions included headache (19%), insomnia (9%), and depression (3%). Emotional lability was reported in 16% of women treated for endometriosis and 6% of children treated for precocious puberty. During postmarketing experience, emotional lability, such as crying, irritability, impatience, anger, and aggression were reported. Depression, including rare reports of suicidal ideation and attempt, were reported 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. Seizures were reported in patients with a history of epilepsy, cerebrovascular disorders, CNS anomalies or tumors, and in patients on concomitant mediations that have been associated with seizures. Additionally, seizures were reported in patients without any risk factors.
In adult women with endometriosis, ovarian cysts have been reported to occur within the first two months of therapy with nafarelin. Many of these events occurred in women with polycystic ovarian syndrome. The cystic ovarian enlargement may resolve spontaneously, usually by about 4-6 weeks of therapy. However, nafarelin discontinuation and/or surgical intervention may be needed in some cases. The relevance, if any, of ovarian cysts in children is unknown. Cases of ovarian hyperstimulation syndrome (OHSS) have been reported during monotherapy use of nafarelin for Assisted Reproductive Technology, an off-label, non-FDA-approved indication. A normally cycling woman developed OHSS after the sole administration of nafarelin nasal spray 400 mcg twice daily starting on day 25 of a spontaneous menstrual cycle. After 14 days of nafarelin receipt, she was evaluated for pituitary desensitization and was diagnosed with OHSS. She had abdominal bloating, breast tenderness, mild nausea, a serum estradiol 10,362 pmol/L, progesterone 6.5 nmol/L, FSH < 1 Units/L, LH 4.2 Units/L, and hCG < 5 Units/L.
In females, nafarelin produces a hypoestrogenic state, which can result in decreased bone mineral density, osteopenia, and osteoporosis during treatment. The increased bone loss may be irreversible. Compared to pretreatment levels, vertebral trabecular bone density decreased an average of 8.7% and total vertebral bone mass decreased an average 4.3% after 6 months of treatment. However, there was partial recovery of trabecular bone density in the post-treatment period; the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively. Total vertebral bone mass decreased by a mean of 5.9% at the end of treatment. The use of GnRH analogs for extended periods of time in adolescent children also causes reduced bone mineral density and osteopenia, potentially leading to osteoporosis. Patients with risk factors for decreased bone mineral density (chronic alcohol abuse and/or tobacco abuse, significant family history of osteoporosis, or chronic use of drugs that may decrease bone mineralization like anticonvulsants or corticosteroids) or a history of decreased bone mineral density may cause additional bone loss; carefully weigh the risks and benefits before nafarelin initiation. The use of nafarelin for longer than the recommended six months in women with endometriosis may cause additional bone loss; repeated courses of treatment with gonadotropin-releasing hormone analogs are not advisable in patients with major risk factors for loss of bone mineral content. Bone loss during one six-month treatment period should not be clinically significant.
Pituitary apoplexy is a syndrome due to a sudden infarction or hemorrhage in the pituitary gland. Pituitary apoplexy is often found in patients with pre-existing pituitary carcinoma. Rare cases of pituitary apoplexy have been reported after the administration of gonadotropin-releasing hormone (GnRH) agonists (such as nafarelin), most commonly in elderly males receiving GnRH agonists in the treatment of advanced prostate cancer, although it has been reported when used for other indications as well. A majority of pituitary apoplexy cases occur within 2 weeks of the first dose and some within the first hour. In these cases, pituitary apoplexy has presented as a sudden and severe headache, nausea and vomiting, visual changes including reduction in visual field (visual impairment) and ocular paresis, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Ocular pain was noted in < 1% of women who received nafarelin. Immediate medical management may be required; management strategies include close observation, corticosteroid administration, maintenance of fluid and electrolyte balance, and possibly surgical decompression of the pituitary fossa.
In men treated with subcutaneous nafarelin for benign prostatic hyperplasia, impotence (erectile dysfunction) is experienced by nearly all patients.
Mean total cholesterol concentrations increased from 191.8 mg/dl (+/- 4.3) at baseline to 204.5 mg/dl (+/- 4.8) at the end of therapy (p < 0.05) among recipients of nafarelin 400 mcg daily. Among patients whose pretreatment total cholesterol values were below 250 mg/dl, 6% had hyperlipidemia defined as post-treatment values above 250 mg/dl. In addition, hypertriglyceridemia (triglyceride concentrations increased above the upper limit of 150 mg/dl) was noted in 12% of patients. At the end of treatment, no patient had abnormally low HDL concentrations (< 30 mg/dl), abnormally high LDL concentrations (> 190 mg/dl), or an increase in the LDL/HDL ratio.
Rhinitis was reported in 5% of children and nasal irritation in 10% of adult women who received nafarelin. No significant effect of rhinitis or nasal congestion on the systemic bioavailability of nafarelin appears to exist; however, if the use of a nasal decongestant for rhinitis is necessary during nafarelin treatment, only use the decongestant >= 2 hours after nafarelin administration.
Palpitations were reported in less than 1% of women receiving nafarelin during clinical trials. During postmarketing surveillance, nafarelin has been associated with reported cases of venous and arterial thromboembolism including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. However, although a temporal relationship was presented in some cases, confounders such as preexisting cardiovascular risk factors and concomitant medications were identified in most cases. At this time, it is uncertain whether a causal relationship exists between these events and gonadotropin-releasing hormone (GnRH) agonists. In October 2010, the FDA announced GnRH agonists, including nafarelin, may increase the risk of diabetes mellitus and certain cardiovascular diseases (e.g. myocardial infarction, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer. The FDA evaluated data from published studies comparing outcomes in patients undergoing androgen deprivation therapy to treat prostate cancer versus patients not undergoing this treatment; most of the studies reported small, but statistically significant, increased risks of diabetes and/or cardiovascular events in men receiving GnRH agonists. At this time, there are no known comparable studies evaluating the risk of diabetes and cardiovascular disease in women or children taking GnRH agonists for other indications. Carefully weigh the known benefits and risks of GnRH agonists when determining appropriate treatment for prostate cancer. Patients receiving GnRH agonists should be monitored for diabetes and cardiovascular events, and risk factors for these events (e.g., smoking, hypertension, hypercholesterolemia, obesity) should continue to be managed according to current clinical practice.
Elevated hepatic enzymes, specifically SGOT and/or SGPT concentrations that were greater than twice the upper limit of normal, were noted in 2 nafarelin recipients. No other clinical or laboratory evidence of abnormal liver function was noted, and transaminase concentrations returned to normal in both patients after nafarelin was stopped. Serious liver injury has been reported post-marketing.
During clinical trials, myalgia occurred in 10% of women receiving nafarelin. Asthenia, arthralgia, and paresthesias were reported in less than 1% of women.
Nafarelin is contraindicated in patients with gonadotropin-releasing hormone (GnRH) analogs hypersensitivity or hypersensitivity to any excipients in nafarelin; anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported.
Nafarelin is contraindicated in patients with undiagnosed abnormal vaginal bleeding. 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 2 months of therapy with nafarelin. Many, but not all, of these events occurred in women with polycystic ovary syndrome (PCOS). These cystic enlargements may resolve spontaneously, generally after about 4 to 6 weeks of therapy, but in some cases may require discontinuation of drug and/or surgical intervention. The relevance to pediatric patients is unknown.
Nafarelin should be used with caution in patients with risk factors for osteoporosis, osteopenia, or other conditions known to decrease bone mineral density (BMD). Chronic nafarelin therapy increases the risk of bone mineral density loss. Repeated courses of nafarelin therapy are not recommended in patients with major risk factors for bone loss; consider the risk; benefit ratio of treatment. Major risk factors should be considered, such as chronic alcohol use and/or tobacco smoking, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroid therapy as these may pose an additional risk.
Use nafarelin with caution in patients with depression and emotional instability, or other psychiatric event. Depression may occur or worsen during treatment with GnRH agonists including nafarelin. 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. Carefully observe for depression, especially in patients with a history of depression and consider whether the risks of continuing nafarelin outweigh the benefits. Individuals with new or worsening depression should be referred to a mental health professional, as appropriate.
Use nafarelin with caution in patients with a preexisting seizure disorder. Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists. These have included patients with a 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 the conditions mentioned.
The safety and efficacy of nafarelin for the treatment of endometriosis in individuals less than 18 years of age has not been established. Nafarelin is approved for use in children for the treatment of central precocious puberty (CPP). Special care is needed for the monitoring of CPP patients to assess both response and compliance, especially during the first 6 to 8 weeks of therapy, to ensure suppression of pituitary gonadal function. Testing may include LH response to GnRH stimulation and circulating gonadal sex steroid levels. Assessment of growth and bone age velocity should begin within 3 to 6 months of therapy initiation. During the first month of treatment, some signs of puberty (vaginal bleeding or breast enlargement) may occur; this is an expected initial effect of the drug. Such changes should resolve soon after the first month. If resolution does not occur within the first 2 months of treatment, consider non-compliance or the presence of gonadotropin-independent sexual precocity. If both possibilities are ruled out, the dose of nafarelin may be increased. Counsel patients and caregivers to assure full compliance with nafarelin dosage as irregular or incomplete compliance with the prescribed dosage may result in stimulation of the pituitary-gonadal axis and reduced efficacy. Also inform patients and caregivers that reports of pseudotumor cerebri (idiopathic intracranial hypertension) have been observed in pediatric patients receiving GnRH agonists. Advise patients and caregivers to monitor for headache and vision issues (such as blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement), ringing in the ears, dizziness, and nausea. Advise patients and caregivers to contact their healthcare provider if any of these symptoms develop.
Nafarelin is contraindicated for use during pregnancy as fetal harm may occur. In animal studies, major fetal abnormalities were observed in rats, but not in mice or rabbits after administration of during the period of organogenesis. There was a dose-related increase in fetal mortality and a decrease in fetal weight in rats and were 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, advise of the potential hazard to the fetus.
Before starting treatment with nafarelin, pregnancy must be excluded in potentially affected individuals (pregnancy testing is recommended). When used regularly at the recommended dose and when patients are compliant with treatment, nafarelin usually inhibits ovulation and stops menstruation, causing menstrual irregularity and is expected to cause temporary infertility in those who might become pregnant. Contraception is not insured, however, by taking nafarelin, particularly if patients miss successive doses. Therefore, contraception requirements are recommended and patients who might become pregnant should use nonhormonal methods of contraception. Such patients should be advised to see their prescriber if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential reproductive risk to the fetus. While use of nafarelin may temporarily affect menstrual cycles, there is no evidence that pregnancy rates are enhanced or adversely affected by the use of naferelin. However, fertility has not been documented by pregnancies and the effect of long-term use is not known. Semen analysis was normal in the 2 ejaculated specimens obtained thus far from boys who have been taken off nafarelin therapy to resume puberty.
It is not known if nafarelin is excreted in human milk. Because of the potential for serious adverse effects to the infant from the hormone-regulating effects of the drug should exposure occur, nafarelin is contraindicated women who are breast-feeding.
Laboratory test interference may occur with nafarelin use. Administration of nafarelin in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 8 weeks after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to 4 to 8 weeks after discontinuation of therapy with nafarelin may be misleading.
For the treatment of endometriosis:
Intranasal dosage:
Adults: 400 mcg intranasally per day administered as 1 spray (note 1 spray = 200 mcg) into one nostril in the morning and 1 spray (200 mcg) into the other nostril in the evening. Start treatment between days 2 and 4 of the menstrual cycle. For those patients that do not achieve amenorrhea after 2 months of 400 mcg/day, may increase dose to 800 mcg intranasally per day administered as 1 spray (200 mcg) in both nostrils every morning and every evening. The usual duration of treatment should not exceed 6 months. However, if symptoms of endometriosis recur after a course of therapy and further treatment with nafarelin is considered, bone density should be assessed. Clinical guidelines/studies suggest that hormonal add-back therapy to nafarelin as an effective means of reducing the bone mineral loss that occurs with nafarelin therapy alone; such therapy does not compromise the efficacy of nafarelin in relieving symptoms and may also reduce vasomotor symptoms and vaginal dryness associated with hypoestrogenism.
For the treatment of uterine leiomyomata*:
Intranasal dosage:
Adult females: 400 mcg intranasally per day administered as 1 spray (note 1 spray = 200 mcg) into one nostril in the morning and 1 spray (200 mcg) into the other nostril in the evening for 3-6 months. Treatment should be started between days 2 and 4 of the menstrual cycle. Other studies indicate a dosage of 800 mcg intranasally per day administered as 1 spray (200 mcg) in both nostrils every morning and every evening. Nafarelin reduces the uterine volume and leiomyoma size; in addition, uterine bleeding and associated hematologic parameters improve with use. Nafarelin can be given before a hysterectomy to reduce fibroid and uterine volume. The use of nafarelin beyond 6 months should be determined based on patient response and osteoporosis risk.
For the treatment of hirsutism*:
Intranasal dosage:
Adult females: 400 mcg intranasally per day administered as 1 spray (note 1 spray = 200 mcg) into one nostril in the morning and 1 spray (200 mcg) into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. Other studies indicate a dosage of 800 mcg intranasally per day administered as 1 spray (200 mcg) in both nostrils every morning and every evening. The use of nafarelin beyond 6 months should be based on patient response and osteoporosis risk. One study of 64 women with hirsutism indicates that combination treatment with an oral contraceptive is more effective than the use of nafarelin alone. The combined use of nafarelin 400 mcg intranasally twice daily and a daily oral contraceptive (norethindrone 1 mg plus ethinyl estradiol 0.035 mg) for 24 weeks was more effective at lowering total testosterone and FSH concentrations and decreasing hair shaft diameter than either agent alone. In addition, combination therapy prevented hot flashes and bone loss that occurred with nafarelin alone.
For inhibiting premature leuteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation and subsequent in vitro fertilization (IVF) or other assisted reproductive technology (ART) for the treatment of infertility*:
NOTE: Drugs such as ganirelix and cetrorelix are now more commonly used and are FDA-approved for this purpose. Nafarelin should only be used by a qualified infertility specialist. Withhold HCG administration in cases where the ovaries are abnormally enlarged to reduce the chance of inducing ovarian hyperstimulation syndrome (OHSS).
Intranasal dosage:
Adult females: Optimal daily dosage is adjusted for the individual patient by the ART specialist; long-protocols are most common but an alternative flare protocol is also used (not discussed here, note the dosage regimens for flare protocols are much different than those of long protocols). In the long protocol, nafarelin is typically started during the midluteal phase (around day 21) of the menstrual cycle prior to the ovarian stimulation cycle; dosages vary but typically range between 400-800 mcg intranasally per day (administered as 200-400 mcg twice daily or 200 mcg 3 times daily). Women will menstruate and continuing to use nafarelin during oocyte stimulation with FSH, which usually begins after estradiol suppression, until hCG administration at follicular maturity. The dose of nafarelin may be decreased at the beginning of ovarian stimulation; one study demonstrated improved numbers of oocytes recovered and a greater number of embryos available for transferring and freezing when the dosage of nafarelin, 200 mcg intranasally 3 times daily, was reduced to 200 mcg intranasally twice daily as ovarian stimulation was initiated.
For the treatment of central precocious puberty:
NOTE: Nafarelin has been designated an orphan drug by the FDA for this indication.
Intranasal dosage:
Children: 400 mcg in each nostril twice daily. Monitor hormonal and clinical parameters during the first 6 to 8 weeks of therapy, as clinically appropriate during therapy, and with dose changes to ensure adequate suppression. In the case of inadequate suppression, the dose may be increased to 600 mcg in alternating nostrils 3 times daily. Max: 1,800 mcg/day.
For the treatment of benign prostatic hyperplasia (BPH)*:
NOTE: Parenteral nafarelin acetate is not currently available in the US.
Subcutaneous dosage:
Adult males: Limited data indicate a dosage of 400 mcg subcutaneously once daily for 6 months. In 9 males with BPH, daily subcutaneous injections of nafarelin decreased serum testosterone concentrations from 14.1 nmol/L to castrate levels within 1 month of therapy initiation. At 4 months, prostate size was decreased by 25% and obstructive symptoms improved. In 3 patients, increases in peak urinary flow rate were clinically significant. All 9 patients were followed for 6 months following nafarelin treatment. At 6 months, the prostate size was 99% of its original weight.
Maximum Dosage Limits:
-Adults
Males: 400 mcg/day SC.
Females: 800 mcg/day intranasally.
-Adolescents
1800 mcg/day intranasally.
-Children
1800 mcg/day intranasally.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Acetaminophen; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Androgens: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Aripiprazole: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Asenapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
atypical antipsychotic: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Brexpiprazole: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Brompheniramine; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Cariprazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Chlorpheniramine; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Chlorpromazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Cimetidine: (Minor) Cimetidine causes hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Clozapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Codeine; Phenylephrine; Promethazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors. (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Codeine; Promethazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Danazol: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Diphenhydramine; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Esterified Estrogens; Methyltestosterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Fluphenazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Guaifenesin; Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Haloperidol: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Iloperidone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Loxapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Lumateperone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Lurasidone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Methyltestosterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Molindone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Olanzapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Olanzapine; Fluoxetine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Olanzapine; Samidorphan: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Oxandrolone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Oxymetazoline: (Moderate) If use of a topical nasal decongestants is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Oxymetholone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Paliperidone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Perphenazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Perphenazine; Amitriptyline: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Phenothiazines: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Phenylephrine: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Pimozide: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Prochlorperazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Promethazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Promethazine; Dextromethorphan: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Promethazine; Phenylephrine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors. (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Quetiapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Risperidone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Testosterone: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
Tetrabenazine: (Moderate) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as tetrabenazine, should not be administered concomitantly with gonadotropin-releasing hormone (GnRH) analogs (nafarelin) since hyperprolactinemia down regulates the number of pituitary GnRH receptors.
Tetrahydrozoline: (Moderate) If use of a topical nasal decongestants is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
Thioridazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Trifluoperazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Ziprasidone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Nafarelin, a synthetic agonistic analog of gonadotropin-releasing hormone (GnRH), has similar actions to endogenous GnRH; nafarelin is nearly 200 times more potent than endogenous GnRH. GnRH, released from the hypothalamus, stimulates receptors on the pituitary gland, which then releases the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Normally, GnRH is released in a pulsatile manner to maintain levels of gonadotropins. Nafarelin, in contrast, is continuously administered, which leads to down-regulation of the GnRH receptor on the pituitary gland and ultimately decreased production of FSH and LH.
-Males: Initially, nafarelin causes increases in serum LH and FSH concentrations with subsequent increases in serum concentrations of testosterone. Chronic administration of nafarelin leads to sustained suppression of pituitary gonadotropins, and testosterone secretion is reduced by approximately the 4th week of treatment; as a result, the tissues and functions that depend on testosterone for their maintenance become quiescent.
-Females: Initial administration of nafarelin stimulates the pituitary gland causing increases in the release of LH and FSH and temporary increases in steroidogenesis. Down-regulation of the pituitary gland by chronic exposure to nafarelin leads to suppression of gonadotropin secretion, and a decrease in serum estradiol levels. These actions reduce ovarian size and function, reduce the size of the uterus and mammary glands, and regress sex hormone-responsive tumors, if present. In most patients, serum LH and FSH are suppressed to follicular phase levels within 4 weeks after initial administration and are usually maintained with continued use. The reversible hypoestrogenic state produces symptomatic relief of the pain of endometriosis, decreases the number of endometriotic lesions, the size of uterine fibroids, and vaginal bleeding associated with uterine fibroids. Following nafarelin discontinuation, as with other hormonal drugs that disrupt the pituitary-gonadal axis, some females may have delayed return to menses. Estradiol, LH, and FSH levels return to pretreatment values within 4-8 weeks following the last administration in most individuals.
-Children: Initial administration of nafarelin stimulates the pituitary gland causing increases in the release of LH and FSH and temporary increases in gonad steroidogenesis. When used regularly in boys and girls with central precocious puberty (CPP) at the recommended dosage, nafarelin suppresses LH and sex steroid hormone levels to prepubertal concentrations within one month of therapy. Consequently, secondary sexual development is arrested and linear growth and skeletal maturation is slowed.
Pharmacokinetics:
Nafarelin is administered topically to the nasal mucosa (intranasally). Approximately 80% of nafarelin is bound to plasma proteins. Six major metabolites of nafarelin have been identified; the activity of these metabolites has not been determined. Furthermore, metabolism of nafarelin by the nasal mucosa has not been determined. The average serum half-life of intranasally administered nafarelin is 3 hours. Drug accumulation was not significant after 22 days of 200 mcg or 400 mcg of twice daily nafarelin.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Approximately 44-55% of a subcutaneous dose is recovered in the urine with 3% recovered as unchanged drug over 7 days following administration; 18.5-44.2% of subcutaneous nafarelin is recovered in the feces.
Other Route(s)
Intranasal route
Systemic absorption following intranasal administration is rapid. Average bioavailability after an intranasal 200 mcg dose is 2.8% (range 1.2-5.6%). Peak serum concentrations occur 10-40 minutes after administration with mean peak serum concentrations of 0.6 ng/mL (range 0.2-1.4 ng/mL) after a 200 mcg dose of intranasal nafarelin and 1.8 ng/mL (range 0.5-5.3 ng/mL) after a 400 mcg dose of intranasal nafarelin.
-Special Populations
Hepatic Impairment
The pharmacokinetics of nafarelin in hepatically impaired patients is unknown.
Renal Impairment
The pharmacokinetics of nafarelin in renally impaired patients is unknown.
Pediatrics
The pharmacokinetics of nafarelin in children is similar to those seen in adults, with a time to peak serum concentration of 10-45 minutes and a serum half-life of 2.5 hours.