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  • CLASSES

    Gonadotropin-Releasing Hormone Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Intranasal synthetic analog of GnRH used for treatment of central precocious puberty in children and for endometriosis, uterine fibroids, and hirsutism in women. Maximum recommended length of therapy in women is 6 months due to risk of osteoporosis. Also used for female infertility.

    COMMON BRAND NAMES

    Synarel

    HOW SUPPLIED

    Synarel Nasal Spray Met: 1actuation, 200mcg

    DOSAGE & INDICATIONS

    For the treatment of endometriosis.
    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. For those patients that do not achieve amenorrhea after 2 months of 400 mcg/day, the dose may be increased to 800 mcg intranasally per day administered as 1 spray (200 mcg) in both nostrils every morning and every evening. The manufacturer of nafarelin does not recommend treatment beyond 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. Bone density values should be within normal limits prior to retreatment. Clinical guidelines/studies suggest that hormonal add-back therapy (e.g., estrogens and/or progestins) 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 endometriosis symptoms and may also reduce vasomotor symptoms and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose, and duration of hormonal therapy have not been established.

    For the treatment of precocious puberty.
    Intranasal dosage
    Children

    1600 mcg intranasally per day administered as 2 sprays (total of 400 mcg) into each nostril every morning and every evening. If adequate suppression cannot be achieved, the dosage may be increased to 1800 mcg intranasally per day administered as 3 sprays (total of 600 mcg) into alternating nostrils 3 times a day.

    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 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Males: 400 mcg/day SC.
    Females: 800 mcg/day intranasally.

    Adolescents

    1800 mcg/day intranasally.

    Children

    1800 mcg/day intranasally.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    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.

    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.

    STORAGE

    Synarel:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Patients and caregivers should be counseled to assure full compliance. Irregular or incomplete daily doses may result in stimulation of the pituitary-gonadal axis.
     
    The bioavailability of intranasal nafarelin did not seem to be significantly affected by rhinitis. However, topical nasal decongestants should not be used until at least 2 hours following the dose of nafarelin. Sneezing during or immediately after dosing should be avoided if possible, as it may inhibit drug absorption. Repeat dosing may be advisable if sneezing occurs.

    Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity

    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.

    Vaginal bleeding

    Nafarelin is contraindicated in women with undiagnosed abnormal vaginal bleeding; such women should receive adequate diagnostic tests before use of this drug.

    Menstruation, pregnancy

    Females should be informed that continued nafarelin therapy interrupts menses and ovulation; women who continue to have cyclic menstruation or who experience breakthrough bleeding should notify their physician. Females of childbearing potential should know that contraception is not ensured by nafarelin therapy, despite interruption of menses; effective non-hormonal contraception must be used by all pre-menopausal females during nafarelin therapy until the return of menses or for at least 12 weeks following discontinuation of therapy. If one or more successive doses of nafarelin are missed, breakthrough bleeding or ovulation may occur with the potential for conception. Due to the effects on hormonal balance, nafarelin is contraindicated in pregnancy (FDA pregnancy risk category X) or in females who may become pregnant; pregnancy should be excluded before starting treatment with nafarelin. Evidence in animals shows an increase in fetal abnormalities and may be dose-related. If pregnancy occurs during treatment, discontinue nafarelin and inform the patient of the potential risk for loss of the pregnancy and fetal abnormalities as a result of the pharmacologic action of the drug.

    Breast-feeding

    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.

    Osteoporosis

    Nafarelin should be used with caution in patients with risk factors for osteoporosis, osteopenia, or other conditions known to decrease bone mineral density. Nafarelin therapy increases the risk of bone mineral density loss, although bone loss during one six-month treatment coarse is not expected to be significant. Repeated courses of nafarelin therapy are not recommended in patients with major risk factors for bone loss. In those patients where a repeated coarse of therapy is considered, bone mineral density should be determined and the drug should only be reinitiated if these parameters are within normal limits. In women, the addition of hormone replacement therapy (estrogens and/or progestins) to GnRH therapy has been effective in reducing the bone mineral loss without compromising the efficacy in relieving endometriosis symptoms.

    Pituitary insufficiency

    Due to nafarelin acetate's suppression of the pituitary-gonadal system, diagnostic tests of pituitary-gonadotropic and gonadal functions (e.g., for pituitary insufficiency) may be misleading during treatment and until the resumption of menses. Normal function is usually restored within 4—8 weeks of stopping nafarelin therapy.

    Children

    The safety and efficacy of nafarelin acetate in children for the treatment of central precocious puberty (CPP) have been established. The diagnosis of central precocious puberty (CPP) must be established before treatment with nafarelin acetate is initiated. Regular monitoring of CPP patients is needed to assess both patient response and compliance, especially during the first 6—8 weeks of therapy to ensure the that suppression of pituitary gonadal function is rapid. Testing may include LH response to GnRH stimulation and circulating gonadal sex steroid levels. Assessment of growth velocity and bone age velocity should begin within 3—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 of these symptoms does not occur within the first 2 months of treatment, first assess the possibility of non-compliance or the presence of gonadotropin independent sexual precocity. If both possibilities are ruled out, the dose of nafarelin may be increased (see Dosage). Safety and efficacy of nafarelin acetate for the treatment of endometriosis in females < 18 years of age has not been established. Furthermore, GnRH analogs have been used alone or added to growth hormone (rh-GH) therapy to moderately increase adult height in adolescents with normally timed puberty and idiopathic short stature. The GnRH-analogs delay puberty and thus prolong the period of bone growth via delay of sex hormone-induced growth-plate senescence. In one study, the use of a GnRH-agonist for 4 years, the typical duration needed to see an increase in adult height, was found to decrease bone mineral density in the lumbosacral region to more than 1 standard deviation below the population mean in 82% of adolescent patients receiving the GnRH-agonist. The authors concluded that GnRH-agonist therapy cannot be routinely recommended to augment height in short adolescents with normally timed puberty; for most adolescents the potential benefit of treatment would not outweigh the risks.

    Depression, suicidal ideation

    Use nafarelin with caution in patients with depression and emotional instability; monitor patients for worsening of psychiatric symptoms during treatment with nafarelin. 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.

    Seizure disorder

    Use nafarelin with caution in patients with a preexisting seizure disorder. Seizures have been reported during postmarketing surveillance in patients with a history of epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with seizures. Seizures have also been reported in patients without any risk factors.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    ovarian hyperstimulation syndrome / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    pituitary apoplexy / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thrombosis / Delayed / Incidence not known

    Moderate

    hot flashes / Early / 3.0-90.0
    hypertriglyceridemia / Delayed / 12.0-12.0
    edema / Delayed / 8.0-8.0
    vaginal bleeding / Delayed / 8.0-8.0
    hyperlipidemia / Delayed / 6.0-6.0
    depression / Delayed / 3.0-3.0
    chest pain (unspecified) / Early / 0-1.0
    dyspnea / Early / 0-1.0
    palpitations / Early / 0-1.0
    impotence (erectile dysfunction) / Delayed / 10.0
    ovarian enlargement / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    libido decrease / Delayed / 21.0-21.0
    headache / Early / 19.0-19.0
    emotional lability / Early / 6.0-16.0
    acne vulgaris / Delayed / 10.0-13.0
    nasal irritation / Early / 10.0-10.0
    myalgia / Early / 10.0-10.0
    insomnia / Early / 9.0-9.0
    breast enlargement / Delayed / 8.0-8.0
    weight gain / Delayed / 8.0-8.0
    seborrhea / Delayed / 3.0-8.0
    weight loss / Delayed / 0-5.0
    rhinitis / Early / 5.0-5.0
    drug-induced body odor / Delayed / 4.0-4.0
    hirsutism / Delayed / 3.0-3.0
    vaginal discharge / Delayed / 3.0-3.0
    libido increase / Delayed / 1.0-1.0
    maculopapular rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    rash / Early / 0-1.0
    ocular pain / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    breakthrough bleeding / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    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; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (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.
    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.
    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.
    Brompheniramine; Carbetapentane; 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; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; Phenylephrine; Pyrilamine: (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.
    Carbinoxamine; Hydrocodone; 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.
    Carbinoxamine; 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.
    Chlophedianol; 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.
    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; Dihydrocodeine; 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; Hydrocodone; 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.
    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.
    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; Hydrocodone; 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.
    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.
    Hydrocodone; 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.
    Loxapine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Meperidine; Promethazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Mesoridazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Molindone: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    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.
    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.
    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.
    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.
    Thiethylperazine: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Females should be informed that continued nafarelin therapy interrupts menses and ovulation; women who continue to have cyclic menstruation or who experience breakthrough bleeding should notify their physician. Females of childbearing potential should know that contraception is not ensured by nafarelin therapy, despite interruption of menses; effective non-hormonal contraception must be used by all pre-menopausal females during nafarelin therapy until the return of menses or for at least 12 weeks following discontinuation of therapy. If one or more successive doses of nafarelin are missed, breakthrough bleeding or ovulation may occur with the potential for conception. Due to the effects on hormonal balance, nafarelin is contraindicated in pregnancy (FDA pregnancy risk category X) or in females who may become pregnant; pregnancy should be excluded before starting treatment with nafarelin. Evidence in animals shows an increase in fetal abnormalities and may be dose-related. If pregnancy occurs during treatment, discontinue nafarelin and inform the patient of the potential risk for loss of the pregnancy and fetal abnormalities as a result of the pharmacologic action of the drug.

    MECHANISM OF ACTION

    Mechanism of Action: 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. 

    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.