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SYNAREL (Nasal Spray)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

SYNAREL (Nasal Spray)

COMPOSITION:
Each bottle contains 60 doses of nafarelin acetate nasal solution (2 mg/mL as nafarelin base), and is supplied with a metered spray pump. Each spray delivers 200 micrograms of nafarelin base. SYNAREL contains benzalkonium chloride 0,1% (m/v) as preservative.

PHARMACOLOGICAL CLASSIFICATION:
A 21.12 Hormone inhibitors.

PHARMACOLOGICAL ACTION:
Nafarelin is an agonistic analogue of gonadotrophin releasing hormone (GnRH). Given as a single dose, nafarelin stimulates release of the pituitary gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), with consequent increase of ovarian and testicular steroidogenesis. During repeated twice daily dosing this response to stimulation gradually diminishes. Within about four weeks, daily administration leads to decreased pituitary gonadotrophin secretion and/or the secretion of gonadotrophins with lowered biological activity. There is a consequent suppression of gonadal steroidogenesis and inhibition of functions in tissues that depend on gonadal steroids for their maintenance.
Nafarelin is rapidly absorbed into the circulation after intranasal administration. Maximum plasma concentration is achieved ten to forty minutes after dosing and the plasma half-life is approximately three hours. Bioavailability of the intranasal dose averages 2,5% (range 1,2 to 5,6%).

INDICATIONS:
SYNAREL is indicated for the hormonal management of endometriosis, including pain relief and reduction of endometric lesions for a period of six months in patients 18 years and older.
SYNAREL is also indicated for use in controlled ovarian stimulation programmes prior to in vitro fertilisation, under the supervision of an infertility specialist.

CONTRA-INDICATIONS:
SYNAREL should not be administered to patients who:

1.	are hypersensitive to GnRH, GnRH agonist analogues or any of the excipients of SYNAREL;
2.	have undiagnosed vaginal bleeding;
3.	are pregnant or may become pregnant as major foetal abnormalities were observed in rats (not applicable when used in in vitro fertilization programmes);
4.	are breast feeding.

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 by breast-feeding women.

WARNINGS:
Loss of trabecular bone mineral content occurs during six months’ treatment with nafarelin. This is usually reversible within six months of stopping treatment. There are no data on the effects of repeat courses on bone loss. Retreatment with SYNAREL or use for longer than six months is, therefore, not recommended (see Side-Effects section on changes in bone density).
Allergic reactions, including anaphylaxis, may occur.
Before starting treatment with SYNAREL pregnancy must be excluded. If a patient becomes pregnant during treatment, administration of the drug must be discontinued and the patient must be informed of a potential risk to foetal development. Patients should use non-hormonal, barrier methods of contraception (not applicable when used in in vitro fertilization programmes).

DOSAGE AND DIRECTIONS FOR USE:
Adults:
SYNAREL is for administration by the intranasal route only.
Endometriosis:
The recommended daily dose of SYNAREL is 200 micrograms taken twice daily as one spray into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days two and four of the menstrual cycle. In clinical studies, women have only received up to six months treatment with SYNAREL. Therefore, the recommended duration of therapy is six months; only one six-month course is advised.
During the first two months of SYNAREL use, some women experience vaginal bleeding of variable duration and intensity. In all likelihood this bleeding represents oestrogen withdrawal bleeding, and is expected to stop spontaneously. If vaginal bleeding continues, the possibility of lack of compliance with the dosing regimen should be considered.
Controlled ovarian stimulation prior to in vitro fertilisation:
In the use of SYNAREL associated with controlled ovarian stimulation prior toin vitro fertilisation, the long protocol should be employed whereby SYNAREL is continued through a period of transient gonadotrophin stimulation lasting 10-15 days (the “flare effect”) through to pituitary desensitisation (down-regulation). Down-regulation may be defined as serum oestradiol <50 pg/mL and serum progesterone <1 ng/mL. The majority of patients down-regulate within 4 weeks.
The recommended daily dose of SYNAREL is 400 micrograms taken twice daily as one spray to each nostril in the morning, and one spray to each nostril in the evening (800 micrograms/day).
Once down regulation is achieved, controlled ovarian stimulation with gonadotrophins e.g. human menopausal gonadotrophin (hMG), is commenced and the SYNAREL dosage maintained until the administration of human chorionic gonadotrophin (hCG) at follicular maturity (usually a further 8-12 days).
If patients do not down-regulate within 12 weeks of starting SYNAREL, it is recommended that SYNAREL therapy be discontinued and the cycle cancelled.
Treatment may begin in either the early follicular phase (day 2) or the mid-luteal phase (usually day 21).
General:
If the use of a nasal decongestant is required at the time of nafarelin administration, it is recommended that the nasal decongestant be used at least thirty minutes after nafarelin dosing.
Sneezing during or immediately after dosing may impair absorption of SYNAREL. If sneezing occurs upon administration, repeating the dose may be advisable.
Each bottle should be used for no more than thirty days. Patients should therefore be advised that continued use after this time may result in delivery of an insufficient amount of nafarelin.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Symptoms suggestive of drug sensitivity, such as shortness of breath, chest pain, urticaria, rash and pruritus have been reported.
The most frequently reported adverse reactions are those related to hypo-oestrogenism; hot flushes, changes in libido, vaginal dryness, headaches, emotional lability, acne, myalgia, decreased breast size, and irritation of the nasal mucosa. Paraesthesia, alopecia, chloasma, asthenia, breast engorgement, arthralgia, insomnia, oedema, seborrhoea, hirsutism, depression and mass gain have been reported.
Changes in Bone Density:
After six months of treatment with SYNAREL, vertebral trabecular bone density and total vertebral bone mass, measured by quantitiative computed tomography (QCT) decreased by an average of 8,7% and 4,3% respectively compared to pretreatment levels. There was partial recovery of 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, measured by dual photon absorptiometry (DPA), decreased by a mean of 5,9% at the end of the treatment. Mean total vertebral mass, re-examined by DPA six months after completion of treatment, was 1,4% 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.
Carcinogenesis/Mutagenesis:
Nafarelin given parentally in high doses to laboratory rodents for prolonged periods induced hyperplasia and neoplasia of endocrine organs, including the anterior pituitary (adenoma/carcinoma) of both mice and rats; tumours of the pancreatic islets, adrenal medulla, testes and ovaries occurred only in long-term studies in rats. No metastases of these tumours were observed. Monkeys treated with high doses of nafarelin for one year did not develop any tumours or proliferative changes. Experience in humans is limited but there is no evidence for tumorigenesis in human beings.
In vitro studies conducted in bacterial and mammalian systems provided no indication of a mutagenic potential for nafarelin.
Impairment of Fertility:
Reproduction studies in rats of both sexes have shown full reversibility of fertility suppression when drug treatment was discontinued after continuous administration for up to six months.
Laboratory Values:
Increased levels of SGOT/SGPT and serum alkaline phosphatase may occur which are reversible on discontinuing treatment. Serum cholesterol and triglyceride levels may increase. Eosinophilia may occur.
Precautions:
When regularly used at the recommended dose, nafarelin inhibits ovulation. In the event of missed doses there may be breakthrough ovulation and a potential for conception. Patients should therefore be advised to use non-hormonal, barrier methods of contraception. Therefore, if a patient becomes pregnant during treatment, administration of the drug must be discontinued and the patient must be informed of a potential risk to foetal development. SYNAREL treatment will be stopped at least three days before fertilised embryos are placed in the uterine cavity.
Controlled ovarian stimulation in in vitro fertilisation:
Pregnancy should be excluded before starting treatment with SYNAREL and the medication should be stopped on the day of administration of hCG. Barrier methods of contraception should be employed whilst SYNAREL is being taken.
Ovarian cysts have been reported to occur in the first two months of therapy with SYNAREL. 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 may require discontinuation of drug and/or surgical intervention.
Controlled ovarian stimulation prior to in vitro fertilisation:
Transient ovarian cyst formation is a recognised complication of GnRH agonist use.
These cysts tend to regress spontaneously over a number of weeks and are more common when GnRH agonists are commenced in the follicular phase of the cycle.
There are no clinical data available on the use of SYNAREL in ovulation induction regimes involving patients with polycystic ovarian syndrome. Caution is advised in this patient group as they are at greater risk of excessive follicular recruitment when undergoing ovulation induction regimes.
Administration of nafarelin in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within eight weeks after treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during the treatment and up to eight weeks after discontinuation of nafarelin therapy may therefore be misleading.
Interactions:
Nafarelin would not be expected to participate in pharmacokinetic-based drug-drug interactions because degradation of the compound is primarily by the action of peptidases not cytochrome P-450 enzymes. Additionally, because nafarelin is only about 80% bound to plasma proteins (albumin), drug interactions at the protein binding level would not be expected to occur.
Rhinitis does not impair nasal absorption of nafarelin. Nasal decongestants used thirty minutes before nafarelin administration decrease absorption.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Treatment should be symptomatic and supportive.

IDENTIFICATION:
SYNAREL is a buffered, clear, colourless to slightly yellow aqueous solution.

PRESENTATION:
Containers containing 60 dose units of 200 mcg nafarelin base per dose.

STORAGE INSTRUCTIONS:
Store upright below 30°C. Protect from light.
Keep out of reach of children.

REGISTRATION NUMBER:
28/21.12/0282

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Searle, Division of Monsanto South Africa (Pty) Ltd
Harrowdene Office Park
Western Service Road
Woodmead X20
Sandton

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
14 October 1995

Updated on this site: January 2005
Source: Pharmaceutical Industry
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