SYNAREL Nasal spray, solution Ref.[7666] Active ingredients: Nafarelin

When regularly used at the recommended dose, nafarelin inhibits ovulation. Patients should be advised to use non-hormonal, barrier methods of contraception. In the event of missed doses there may be breakthrough ovulation and a potential for conception. 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 fetal development and/or miscarriage. As there is a risk of miscarriage in the patient population, a causal association with nafarelin acetate is uncertain. NB Synarel treatment will be stopped at least 3 days before fertilised embryos are placed in the uterine cavity.

As with other drugs in this class 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.

After a course of therapy, if further treatment of endometriosis and fibroids with nafarelin acetate is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

In adults, after six months of nafarelin acetate treatment there was very little, if any, decrease in the mineral content of the distal radius and second metacarpal. There was a reduction in vertebral trabecular bone density and total vertebral mass, averaging 8.7% and 4.3%, respectively. Substantial recovery of bone occurred during the post-treatment period. Total vertebral bone mass, measured by dual photon absorptiometry (DPA) decreased by a mean of 5.9% at the end of treatment. Mean total vertebral mass, re-examined by DPA six months after completion of treatment, was 1.4% below pretreatment levels.

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 regimens 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 8 weeks after treatment is discontinued. Diagnostic tests of pituitary-gonadal function conducted during the treatment and up to 8 weeks after discontinuation of nafarelin therapy may therefore be misleading.

Sneezing during or immediately after dosing may impair absorption of nafarelin acetate. If sneezing occurs upon administration, repeating the dose may be advisable.

If the use of a nasal decongestant is required, it is recommended that the nasal decongestant be used at least 30 minutes after nafarelin acetate dosing (see Section 4.5).

Nafarelin acetate contains the preservative benzalkonium chloride, which may cause contractions of the respiratory passage. The preservative (benzalkonium chloride) in nafarelin acetate may cause oedemas in the nasal mucosa, especially on long term use. If a persistent oedema in the nasal mucosa is suspected, a medicinal product for nasal use without preservative should be chosen, if possible. If such products for nasal use are not available, the use of other formulations of the medicinal product should be considered.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as nafarelin acetate. Patients should be informed accordingly and treated as appropriate if symptoms occur.

No pharmacokinetic-based drug-drug interaction studies have been conducted with nafarelin acetate. 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) 4°C, drug interactions at the protein-binding level would not be expected to occur.

Rhinitis does not impair nasal absorption of nafarelin. The use of the decongestant oxymetazoline hydrochloride by subjects with perennial rhinitis 30 minutes prior to nafarelin acetate administration significantly reduced the extent of nasal absorption of nafarelin acetate (39% decrease in AUC_0-8h; 49% decrease in C_max) compared to the absorption attained in subjects with normal nasal mucosa. The concomitant use of decongestants should be discouraged in patients receiving nafarelin acetate (see Section 4.4.).

When administered intramuscularly to rats on days 6-15 of pregnancy at doses of 0.4, 1.6 and 6.4 mcg/kg/day (0.6, 2.5 and 10.0 times the intranasal human dose of 400mcg per day), 4/80 fetuses in the highest dose group had major fetal abnormalities that were not seen in a repeat study in rats. Moreover, studies in mice and rabbits failed to demonstrate an increase in fetal abnormalities. In rats, there was a dose-related increase in fetal mortality, and a decrease in fetal weight with the highest dose. These effects on rat fetal mortality are logical consequences of the alterations in hormonal levels brought about by nafarelin in this species.

Use of nafarelin in human pregnancy has not been studied.

Synarel should not therefore be used during pregnancy or suspected pregnancy. 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 fetal development. (see Section 4.3).

Controlled ovarian stimulation prior to 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.

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. (see Section 4.3).

Not applicable.

Initial treatment with nafarelin acetate may cause transient exacerbation of endometriosis and chronic treatment may induce a menopausal state. The following undesirable effects have been observed and reported during treatment of 282 adult patients with nafarelin acetate with the following frequencies: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Not known: Cannot be estimated from the available data.

Immune system disorders

Common: Drug hypersensitivity (Chest pain, Dyspnoea, Pruritus, Rash, Urticaria)

Endocrine disorders

Common: Oestrogen deficiency

Metabolism and nutrition disorders

Very common: Weight increased

Common: Weight decreased

Psychiatric disorders

Very common: Affect lability, Libido decreased

Common: Depression, Insomnia, Libido increased

Nervous system disorders

Very common: Headache

Common: Paraesthesia

Vascular disorders

Very common: Hot flush

Common: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders

Very common: Rhinitis

Skin and subcutaneous tissue disorders

Very common: Acne, Seborrhoea

Common: Hirsutism

Uncommon: Alopecia

Musculoskeletal and connective tissue disorders

Very common: Myalgia

Uncommon: Arthralgia

Reproductive system and breast disorders

Very common: Breast atrophy, Vulvovaginal dryness

Common: Artificial menopause, Uterine haemorrhage

Uncommon: Breast enlargement, Ovarian cyst

Not known: Ovarian hyperstimulation syndrome

General disorders and administration site conditions

Very common: Oedema

Investigations

Common: Bone density decreased

In addition to the above mentioned undesirable affects, migraine, blurred vision, palpitations, shortness of breath, increased levels of SGOT/SGPT and serum alkaline phosphatase have been reported but the frequencies are not known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None stated.