Synarel

Gonadotropin-Releasing Hormone Agonists

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.

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.

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

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

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

Synarel

Rx

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.

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.

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.

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.

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.

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.

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

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

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

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.
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; 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.
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; 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; 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.
Loxapine: (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.
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.

Synarel Nasal Spray Met: 1actuation, 200mcg

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

1800 mcg/day intranasally.

1800 mcg/day intranasally.

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.

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. 

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.

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.

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.