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SYNAREL is a brand name for Nafarelin, supplied as a metered-dose aerosol. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................3 WARNINGS AND PRECAUTIONS…
Verbatim from this product's HC label. Tap a section to expand.
Recommended Dose and Dosage Adjustment For the management of endometriosis, the recommended daily dose of Synarel (nafarelin acetate) is 400 μg. This is achieved by one spray (200 μg of nafarelin free base) into one nostril in the morning and one spray into the other nostril in the evening.
Treatment should be started between days 2 and 4 of the menstrual cycle. In an occasional patient, the 400 μg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of Synarel may be increased to 800 μg daily.
The 800 μg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening. The recommended duration of administration is six months. The safety of retreatment as well as of treatment beyond 6 months with nafarelin has not yet been established.
If the symptoms of endometriosis recur after a course of therapy, and further treatment with Synarel is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
If the use of a topical nasal decongestant is necessary during treatment with Synarel, the decongestant should not be used until at least 30 minutes after Synarel dosing (see DRUG INTERACTIONS). At 400 μg/day, an 8 mL bottle of Synarel provides a 30 day supply (about 60 sprays).
If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre.
12 ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Nafarelin is an agonistic analogue of the gonadotropin releasing hormone (GnRH). Given as a single intranasal dose, nafarelin stimulates release of the pituitary gonadotropins, LH and FSH, with consequent increase of ovarian steroidogenesis.
Repeated intranasal dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration of 200 μg, as a nasal spray, leads to decreased secretion of gonadal steroids by about 4 weeks. Consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent.
Pharmacodynamics General The effects of a single 500 μg IN dose of nafarelin on the secretion of LH were investigated in six women who previously had had hysterectomies. 5 μg given at approximately weekly intervals. Serum LH concentrations increased to peak levels 5- to 40-fold higher than predosing baseline levels after 500 μg IN nafarelin.
As would be expected with a drug which lowers serum estradiol levels, the most frequently reported adverse reactions were those related to hypoestrogenism. Adverse events associated with the hypoestrogenic state induced by Synarel, occurred in clinical studies.
The most frequently reported adverse events were hot flashes (90%), decrease in libido (22%), headache (19%), vaginal dryness (19%), emotional lability (15%), acne (13%), myalgia (10%) and reduction in breast size (10%). Estrogen levels returned to normal after treatment was discontinued with resolution of the hypoestrogenic effects.
Nasal irritation occurred in about 10% of all patients who used intranasal nafarelin. Controlled studies included 203 evaluable women (mean age 32 years) treated on average for 170 days with Synarel (nafarelin acetate) 400 μg/day. The adverse reactions most frequently reported and thought to be drug related are tabulated below.
2% of adult patients, symptoms suggestive of drug sensitivity, such as chest pain, pruritus, rash, shortness of breath and urticaria have occurred. 3%, respectively, compared to pretreatment levels. 3% less than the pretreatment levels, respectively.
9% at the end of treatment. 4% below pretreatment levels. There was little, if any, decrease in the mineral content in compact bone of the distal radius and second metacarpal. Use of Synarel for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.
There are no data in changes in bone density in children.
Plasma enzymes:
After 6 months of therapy with 400 μg/day of Synarel, elevations in SGOT outside the normal range were observed in 5 (3%) of 180 patients with normal baseline values. Post treatment evaluations were available for 4 of these patients: the level of SGOT was within the normal range.
General Retreatment:
The safety of retreatment as well as of treatment beyond 6 months with Synarel has not yet been established, and therefore retreatment cannot be recommended. Carcinogenesis and Mutagenesis As seen with other GnRH agonists, high parenteral doses (up to 100 μg/kg/day in mice for 18 months and 500 μg/kg/day in rats for 24 months) induced hyperplasia and/or neoplasia (without metastasis) of endocrine organs including the pituitary (adenoma/carcinoma).
Rodents are particularly sensitive to hormonal stimulation when tested for tumourigenicity. No evidence of tumorigenicity has been reported in monkeys or man. No indication of a mutagenic potential for nafarelin has been reported.
Endocrine and Metabolism Bone Density:
The induced hypoestrogenic state caused by Synarel, results in a small loss in bone density over the course of treatment, some of which may not be reversible. During one six- month treatment period, this bone loss should not be important.
In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, Synarel therapy may pose an additional risk.
In these patients, the risks and benefits must be weighed carefully before therapy with Synarel is instituted. Repeated courses of treatment with gonadotropin releasing hormone analogues are not advisable in patients with major risk factors for loss of bone mineral content.
Genitourinary Isolated cases of short-term worsening of signs and symptoms or enlargement of ovarian cysts have been reported during initiation of nafarelin acetate therapy: they are sometimes, but not necessarily, associated with a stimulation of the pituitary gland and an initial increase in the levels of circulating gonadal hormones.
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Serum LH levels also increased in response to each of the lower doses in at least three of the four women. 5 μg dose, thus indicating that the analog was extremely potent in that very low concentrations (< 50 pg/mL) were sufficient to stimulate the release of LH.
Most importantly this study demonstrated that nasal administration of nafarelin might be suitable for clinical applications. Gonadotropin-Ovarian Responses to 90 or 180 Day Administration of Intranasal Nafarelin In a single-center, open, parallel, nonrandomized investigation, fifteen healthy volunteers were enrolled to study ovulation inhibition (Part A) and nine additional women with endometriosis were enrolled to study their gonadotropin-ovarian response (Part B).
Four doses of IN nafarelin (formulated at three different concentrations) were employed. 5 mg/mL spray) daily for three months. 5 mg/mL, expressed as the acetate salt) of nafarelin twice a day for six months. A dose of 500 μg of nafarelin acetate corresponds to a 400 μg dose of nafarelin base.
In all women receiving nafarelin once a day there was little, or at most, inconsistent desensitization of pituitary gonadotropes. There was generally a large, acute increase in serum gonadotropin levels after each dose of nafarelin, which peaked within 2 to 4 hours.
In most instances, the acute release of LH and FSH induced a similar, but somewhat delayed, increase in serum concentrations of E2. Although there was only partial pituitary desensitization, some dose-dependent changes in ovarian function were observed.
Mean E2 concentrations during the third treatment month were either comparable to (125 and 250 μg dose groups) or below (500 μg dose group) pretreatment values. 13 The pituitary responses to 1000 μg nafarelin (500 μg twice a day) were quite different.
There was a small, but significant, decrease in basal levels of both LH and FSH. In addition, there was almost complete desensitization of the pituitary gonadotropes with only small and inconsistent increases in serum levels of LH and FSH in response to drug administration.
Mean basal concentrations of E2 decreased to less than 30 pg/mL by the fourth week of treatment. The effects of nafarelin administration upon ovulatory ovarian function were dose related. Inhibition of ovulation correlated with the degree of suppression of estradiol secretion.
, women receiving 1000 μg nafarelin/day), ovulation was reliably inhibited. The most common complaint in the women receiving nafarelin, hot flashes, resulted from hypoestrogenemia. They were reported by one subject in each of the 125, 250, and 500 μg/day groups and by all patients receiving 1000 μg/day.
Effects of 500 μg of Nafarelin Acetate Every 12 Hours Upon Endometriosis The effects of nafarelin treatment on the symptoms and severity of endometriosis (measured according to the American Fertility Society scoring system) were assessed in the patients in Part B of the clinical study described above.
There was a […]
For SGPT, 2 (3%) of 68 patients with normal baseline had increases outside the normal range. 1 patient, for which data are available, returned to normal during the post-treatment observation. For alkaline phosphatase, 10 (5%) out of 182 patients with normal baseline level had increases outside the normal range at the end of treatment.
Post treatment evaluations were available for 8 of these patients: 4 patients were within the normal range, the other 4 patients were above the normal range but this was not considered clinically significant.
Lipids:
At enrollment, 9% of the patients receiving Synarel 400 μg/day had total cholesterol values above 250 mg/dL. These patients also had cholesterol values above 250 mg/dL at the end of treatment. Of those patients whose pretreatment cholesterol values were below 250 mg/dL, 6% in the Synarel group, had post-treatment values above 250 mg/dL.
3) mg/dL. 8) mg/dL. 05). 9 Triglycerides were increased above the upper limit of 150 mg/dL in 12% of the patients who received Synarel. Following completion of treatment, no patients receiving Synarel had abnormally low HDL cholesterol fractions (less than 30 mg/dL) and none of the patients receiving Synarel had abnormally high LDL cholesterol fractions (greater than 190 mg/dL).
There was no increase in the LDL/HDL ratio in patients receiving Synarel.
Other:
In comparative studies, the following changes were seen in approximately 10% to 15% of patients. Synarel treatment was associated with elevations of plasma phosphorous and eosinophil counts, and decreases in serum calcium and WBC counts.
Post-Market Adverse Drug Reactions Cardiac disorders:
Myocardial infarction.
Endocrine disorders:
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists.
In a majority of these cases, a pituitary adenoma was diagnosed, […]
Many, but not all, of these events occurred in patients with polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by about four to six weeks of therapy, but in some cases, worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.
Sexual Function/Reproduction Since menstruation should stop with effective doses of Synarel, the patient should notify her physician, if regular menstruation persists. Patients missing successive doses of Synarel may experience break through vaginal bleeding.
Use of Synarel in human pregnancy has not been studied. After 6 months of therapy with Synarel, 56 patients, who were treated with 400 μg/day, desired and attempted pregnancy. By the end of 18 months post treatment, 17 (30%) patients became pregnant.
In the 800 μg/day 5 group, out of 48 patients attempting pregnancy, 25 of them (52%) became pregnant within 18 months post treatment. Full term delivery occurred in 82% and 68% of patients in the 400 and 800 μg/day groups respectively.
All newborns were normal except for one male baby who had hydrocele. The mother of the baby was in the 400 μg/day group. The serum concentration of gonadotropins and estradiol returned promptly to normal after cessation of therapy.
Special Populations Pregnant Women:
Safe use of Synarel (nafarelin acetate) in pregnancy has not been established clinically. Patients should not use Synarel if they are pregnant or suspected to be pregnant. Before starting treatment with Synarel, pregnancy must be excluded.
When used regularly at the recommended dose, Synarel usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking Synarel, particularly if patients miss successive drug doses. Patients should be advised that if they miss successive doses of Synarel, ovulation may occur with the potential for conception.
Therefore, PATIENTS SHOULD USE NONHORMONAL METHODS OF CONTRACEPTION DURING TREATMENT. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued, and the patient must be informed of the potential risk to fetal development.
There is no experience with Synarel in pregnant women.
Nursing Women:
It is not known whether or to what extent nafarelin is excreted into human breast milk. The effects, if any, on the breast-fed child have not been determined and therefore Synarel should not be used in breast feeding women.
Pediatrics:
The safety and effectiveness of Synarel in children have not been established and therefore Synarel should not be used.
Hepatic or renal impairment:
There is no information on SYNAREL in patients with hepatic or renal insufficiencies. For animal data, see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics.