SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Suprecur 150 micrograms Nasal Spray Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Suprecur nasal spray contains 150 micrograms buserelin, as buserelin acetate, in one spray dose.

150 micrograms buserelin is equivalent to 157.5 micrograms buserelin acetate.

For full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Nasal Spray Solution

The preparation is a clear solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of endometriosis in cases that do not require surgery as primary therapy.

Pituitary desensitisation in preparation for ovulation induction regimens using gonadotrophins.

4.2 Posology and method of administration

Endometriosis: The total daily dose is 900 micrograms buserelin, administered as one spray dose in each nostril in the morning, at mid-day and in the evening. The product may be used before or after meals or at other times, provided that uniform intervals are maintained between doses.

The usual duration of treatment is six months and this should not be exceeded. Only a single course of treatment is recommended.

Repeated courses of treatment must only be administered after a careful review of the risk/benefit ratio by the attending physician since the possibility of additive effects on bone mass (reduction in bone mass) cannot be excluded (see also section 4.4).

Pituitary desensitisation prior to ovulation induction: The total daily intranasal dose for this indication is 600 micrograms buserelin, given in four divided dosages of 150 micrograms (one application in one nostril) spread over the waking hours. Treatment should start in the early follicular phase (day 1) or, provided the existence of an early pregnancy has been excluded in the midluteal phase (day 21). It should continue at least until down-regulation is achieved e.g. serum estradiol <50 ng/l and serum progesterone <1 microgram/l. This will usually take about 2-3 weeks. In some patients, dosages up to 4 x 300 micrograms may be required to achieve these levels. When down-regulation is achieved, stimulation with gonadotropin is commenced while the dosage of buserelin is maintained. At the appropriate stage of follicular development, gonadotropin and buserelin are stopped and hCG is given to induce ovulation.

Treatment monitoring, oocyte transfer and fertilisation techniques are performed according to the normal practice of the individual clinic.

Luteal support with hCG or progesterone should be given as appropriate.

If used correctly, reliable absorption of the active ingredient takes place via nasal mucous membranes. The drug is absorbed even if the patient has a cold; however, in such cases the nose should be blown thoroughly before administration.

If nasal decongestants are being used concurrently, they should be administered at least 30 minutes after the buserelin.

Children: Suprecur is not suitable for use in children.

Elderly: Suprecur is not suitable for use in post-menopausal women.

4.3    Contraindications

Buserelin should not be used if the tumour is found to be insensitive to hormone manipulation, after surgical removal of the testes or in cases of undiagnosed vaginal bleeding. It is contraindicated in cases of known hypersensitivity to benzalkonium chloride, LHRH or buserelin. It should not be used during pregnancy or lactation (see 4.6 Pregnancy and lactation).

4.4    Special warnings and precautions for use

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as Buserelin. Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients known to suffer from depression should be carefully monitored and treated if necessary during treatment with Suprecur (risk of recurrence or worsening of depression).

In patients with hypertension, blood pressure must be checked regularly (risk of deterioration of blood pressure levels).

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Suprecur.

The use of LHRH-agonists may be associated with decreased bone density and may lead to osteoporosis and an increased risk of bone fracture (see section 4.8). Particular caution is necessary in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with anticonvulsants or corticosteroids or a family history of osteoporosis) it is recommended to periodically monitor bone mineral density (BMD) and use preventative measures during therapy to prevent osteopenia/osteoporosis.

In some patients treated with GnRH-agonists, change in glucose tolerance is observed (see section 4.8). In diabetic patients blood glucose levels must be checked regularly (risk of deterioration of metabolic control).

Endometriosis: Patients should discontinue oral contraceptives before starting treatment. Where appropriate, alternative, non-hormonal methods of contraception should be used. If treatment is interrupted even for only a few days, ovulation may occur and there is a risk of pregnancy.

Suprecur treatment should be started on the first or second day of menstruation in order to exclude pre-existing pregnancy as far as possible. A pregnancy test is advisable if there is any doubt.

It is not expected that pregnancy will occur during the course of the treatment if the recommended doses are taken regularly. However, if treatment is interrupted for only a few days, ovulation and pregnancy may occur. If pregnancy does occur, treatment with buserelin must be discontinued immediately and a physician must me informed (see also section 4.6).

Repeated courses of treatment must only be administered after a careful review of the risk/benefit ratio by the attending physician since the possibility of additive effects on bone mass (reduction in bone mass) cannot be excluded (see also section 4.8). A course of treatment with buserelin lasting several months may lead to loss of bone mineral content. For this reason the recommended maximal duration of treatment should be 6 months.

A menstruation-like bleed usually occurs during the first few weeks of treatment. Breakthrough bleeding may also occur during continuing courses of treatment in some patients. Recovery of pituitary-gonadal function usually occurs within 8 weeks of discontinuing treatment.

In the initial treatment with buserelin, ovarian cysts may develop.

Pituitary desensitisation prior to ovulation induction:

Before treatment is started, it is recommended that a pregnancy test be performed.

Induction of ovulation should be carried out under close medical supervision. Risks specific to IVF/ET and related assisted reproduction procedures such as increase in miscarriages, ectopic and multiple pregnancies are unaltered under adjunctive use of buserelin. In addition, follicle recruitment may be increased especially in patients with PCOD.

Combined use of buserelin with gonadotropins may bear a higher risk of ovarian hyperstimulation syndrome (OHSS) than the use of gonadotropins alone.

In patients with polycystic ovarian syndrome, caution is recommended, because there is an increased tendency towards ovarian hyperstimulation syndrome when combined with gondatropins.

Possible clinical signs of ovarian hyperstimulation syndrome (OHSS) include: abdominal pain, feeling of abdominal tension, increased abdominal girth, occurrence of ovarian cysts, nausea, vomiting, as well as massive enlargement of the ovaries, dyspnoea, diarrhoea, oligurea, haemoconcentration, hypercoagulability. Pedicle torsion or rupture of the ovary may lead to an acute abdomen. Severe thromboembolic events may also occur. Fatal outcome is possible.

The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS. hCG should be withheld if necessary.

Ovarian cysts have been observed in the initial phase of buserelin treatment. No impact on the stimulation cycle has been reported so far.

Treatment with Suprecur should be initiated only under the supervision of a specialist with experience of the indication.

4.5 Interaction with other medicinal products and other forms of interaction

During treatment with buserelin, the effect of antidiabetic agents may be attenuated.

In concomitant treatment with sexual hormones ("add back"), the dosage is to be selected so as to ensure that the overall therapeutic effect is not affected.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Suprecur with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Suprecur is contraindicated in pregnancy and lactation. In rats, fetal malformations have been seen after very high doses.

Buserelin passes into breast milk in small amounts. Although negative effects on the infant have not been observed, it is recommended that breast-feeding be avoided during treatment with Suprecur in order to prevent the infant from ingesting small quantities of buserelin with breast milk.

In endometriosis: It is unlikely that pregnancy will occur in the later stages of treatment if the recommended doses are taken regularly. However, if treatment is interrupted even for only a few days, ovulation may occur and the patient may become pregnant. In this event, Suprecur must be withdrawn immediately and a physician must be informed (see also section 4.4).

In pituitary desensitisation prior to ovulation induction: Pregnancy should be excluded before starting Suprecur, and the medication should be stopped on the day of administration of hCG.

4.7 Effects on Ability to Drive and Use Machines

Certain adverse effects (e.g. dizziness) may impair the patients ability to concentrate and react, and therefore, constitute a risk in those situations where these abilities are of special importance (e.g. operating a vehicle or machinery).

4.8 Undesirable effects

The following CIOMS frequency rating is used: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10 000 to <1/1000); very rare (<1/10 000), not known (cannot be estimated from the available data).

In isolated cases severe hypersensitivity reactions with shock can occur. These may become manifest as, e.g. reddening of the skin, itching, skin rashes (including urticaria) and allergic asthma with dyspnoea as well as, in isolated cases leading to anaphylactic/anaphylactoid shock.

The nasal spray may irritate the nasal mucosa, leading to nosebleeds and hoarseness as well as to disturbances of smell and taste.

Treatment with buserelin inhibits oestrogen production. As evidence of the biological response to hormone deprivation, patients may experience menopausal-like symptoms and withdrawal bleeding, which are directly related to the pharmacological action of the drug. Symptoms such as hot flushes, increased sweating, dry vagina, dyspareunia, loss of libido generally

occur some weeks after starting treatment and may be severe in some patients. Withdrawal bleeding may occur during the first few weeks of treatment. Breakthrough bleeding may occur during continuing treatment. After several months’ treatment, a decrease in bone mass may occur.

Changes in bone density: A decrease in bone mineral, the magnitude of which relates to the duration of therapy, occurs during treatment with buserelin alone. The evidence available indicates that six months' treatment is associated with a decrease in bone mineral density of the spine of 3.5%. These changes are similar to those seen with other agonists. Increased levels of serum alkaline phosphatase may occur. These are reversible on discontinuing treatment.

Buserelin treatment may also lead to:

Neoplasms benign and malignant - Very rare cases of pituitary adenomas were reported during treatment with LH-RH agonists, including buserelin.

Blood disorders - Very rare cases of thrombocytopenia or leucopenia.

Metabolism and nutrition disorders - Frequent increase or decrease in weight. Occasional changes in appetite and increased thirst. Rarely increase or decrease in blood lipid levels. Very rarely, reduction in glucose tolerance which may lead to the worsening of metabolic control in diabetics.

Psychiatric disorders - Frequent nervousness, emotional instability.

Occasional anxiety, depression or worsening of existing depression.

Mood changes, depression. Frequency:    Long term use: common

Short term use: Uncommon

Nervous system disorders - Dizziness, headache (in women in rare cases migraine-like), sleep disturbances, tiredness, drowsiness. Occasional paraesthesia (especially in the arms and legs), disturbances of memory and concentration.

Eye disorders - Occasional dry eyes (possibly leading to eye irritations in people who wear contact lenses), impaired vision (e.g. blurred vision), feeling of pressure behind the eyes.

Ear and labyrinth disorders - Rare cases of tinnitus, hearing disorders found.

Cardiac disorders - Frequent palpitations.

Frequency unknown: QT prolongation (see sections 4.4 and 4.5)

Vascular disorders - Occasional oedema (of face and extremities) and hot flushes. Very rare cases of a deterioration of blood pressure levels in patients with hypertension.

Gastrointestinal disorders - Frequent lower abdominal pain, stomach ache, nausea, vomiting, diarrhoea, constipation.

Hepato-biliary disorders - Occasional increase in serum liver enzyme levels (e.g. transaminases), increase in serum bilirubin.

Skin and subcutaneous tissue disorders - Frequent dry skin, acne, increase or decrease in scalp hair (alopecia, hirsutism). Occasional increase or decrease in body hair, splitting nails.

Musculoskeletal and bone disorders - Frequent musculoskeletal discomfort and pain (including shoulder pain/stiffness). The use of LHRH-agonists may be associated with decreased bone density and may lead to osteoporosis and an increased risk of bone fracture. The risk of skeletal fracture increases with the duration of therapy.

Reproductive system and breast disorders - Frequent Vaginal discharge, increase or decrease in breast size, breast tenderness. Occasional lactation.

In the initial phase of treatment with buserelin, ovarian cysts may develop (see also section 4.4). For preparation of ovulation induction, however, no negative effect on the course of stimulation has been reported so far.

In-vitro fertilization/embryo transfer programmes and similar assisted reproduction procedures carry inherent risks, e.g. increased occurrence of ectopic pregnancies, miscarriages or multiple pregnancies; this also applies where buserelin is used as adjunctive therapy. The fact that follicle recruitment may be increased under buserelin treatment (especially in the case of polycystic ovaries) may, however, in some patients also represent a desirable effect.

Combined use of buserelin with gonadotropins may bear a higher risk of ovarian hyperstimulation syndrome (OHSS) than the use of gonadotropins alone (see also section 4.4).

Degeneration of uterine fibroids in women with uterine fibroids.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdose may lead to signs and symptoms such as asthenia, headache, nervousness, hot flushes, dizziness, nausea, abdominal pain, oedema of the lower extremities and mastodynia. Treatment should be symptomatic.

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: Hormones and Related Agents ATC Code: L02AE01

Buserelin is a synthetic peptide. It is a superactive analogue of natural gonadotrophin releasing hormone (gonadorelin, LHRH or GNRH). After an initial stimulation of gonadotrophin release, it down-regulates the hypothalamic-pituitary-gonadal axis.

5.2    Pharmacokinetic properties

The intra-nasal absorption rate of buserelin is about 3%. Metabolic inactivation by peptides occurs in the liver and kidney. The drug is also inactivated by pituitary membrane enzymes. After intra-nasal administration to humans, buserelin is excreted for more than 8 hours in the urine. Virtually all the serum fraction, and half the urine fraction of buserelin, are present as the parent drug.

The bioavailability of buserelin after nasal administration is not adversely influenced by the presence of rhinitis.

5.3 Preclinical safety data

None of clinical relevance.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The nasal spray also contains citric acid, sodium citrate, sodium chloride and benzalkonium chloride in aqueous solution.

6.2 Incompatibilities

None.

Shelf life

3 years. 5 weeks after first opening.

6.4 Special precautions for storage

Store between 2 and 25°C. Do not freeze.

6.5 Nature and contents of container

Cartons containing two bottles and two metered-dose pumps (nebulisers). Each bottle contains l0g solution.

6.6 Instructions for use/handling

How to use the spray bottle:

1.    Remove screw cap from bottle.

2.    Remove metered-dose nebulizer from transparent plastic container and take off

both protective caps.

3.    Screw nebulizer on to bottle.

4.    Before first application only, pump 5-8 times, holding bottle vertical, until the

solution has filled the system and a uniform spray is emitted. The preliminary pumping is for the purpose of filling the system and testing the spray. It must not be repeated after the first use, in order to avoid wasting the contents.

5.    Keeping bottle vertical and bending head over it slightly, spray solution into nose.

If necessary, the nose should be cleaned before applying the solution.

6.    After use leave nebulizer on bottle. After replacing protective cap, spray bottle is best stored in its transparent container in an upright position.

MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited One Onslow Street Guildford Surrey

GU1 4YS UK

or trading as:-

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04425/0277

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first Authorisation: 23 April 2002 Date of latest Renewal: 20 January 2005

10    DATE OF REVISION OF THE TEXT

19/02/2015