SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

SUPREFACT NASAL SPRAY

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Suprefact nasal spray contains 100 micrograms buserelin as buserelin acetate in 1 spray dose of aqueous solution containing benzalkonium chloride as preservative.

100 micrograms buserelin is equivalent to 105 micrograms buserelin acetate.

3    PHARMACEUTICAL FORM

Nasal spray

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of advanced hormone dependent prostatic carcinoma (stage C or stage D according to the classification of Murphy et al. in Cancer, 45, p 1889-95, 1980) in which suppression of testosterone is indicated; however, not after bilateral orchiectomy (no further reduction of testosterone level by buserelin to be expected).

Buserelin acts by blockade and subsequent down-regulation of pituitary LHRH receptor synthesis. Gonadotropin release is consequently inhibited. As a result of this inhibition there is reduced stimulation of testosterone secretion and serum testosterone levels fall to the castration range. Before inhibition occurs there is a brief stimulatory phase during which testosterone levels may rise.

4.2. Posology and Method of Administration

Initiation of therapy: is most conveniently carried out in hospital; 0.5 ml Suprefact injection should be injected subcutaneously at 8 hourly intervals for 7 days.

Maintenance therapy: on the 8th day of treatment the patient is changed to intranasal administration of Suprefact. One spray dose is introduced into each nostril 6 times a day according to the following schedule:

1st dose before breakfast

2nd dose after breakfast

3rd and 4th doses before and after midday meal

5th and 6th doses before and after evening meal.

This dosage regimen is to ensure adequate absorption of the material and to distribute the dose throughout the day.

If used correctly, reliable absorption of the active ingredient takes place via nasal mucous membranes. Suprefact nasal spray is absorbed even if the patient has a cold.

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

4.3. Contra-indications

Suprefact should not be used if the tumour is found to be insensitive to hormone manipulation or after surgical removal of the testes. It should not be used in pregnancy. It is contra-indicated in cases of known hypersensitivity to benzalkonium chloride or buserelin.

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 with a history of depression must be carefully monitored and treated if necessary during treatment with Suprefact (risk of recurrence or worsening of depression).

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

QT Prolongation

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 Suprefact.

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).

The effect can be monitored clinically and by determination of prostate specific antigen (PSA) and testosterone in the serum. Testosterone levels increases in the beginning of the treatment and thereafter decreases during two weeks. After two to four weeks, the testosterone levels have decreased to castration level.

Disease flare (temporary deterioration of patient's condition) has been reported at the beginning of treatment. The incidence is variable, but of the order of 10%. Symptoms are usually confined to transient increase in pain, but the exact nature depends on the site of the lesions.

Disease flare is prevented by the prophylactic use of an anti-androgen so it is strongly recommended that administration of an anti-androgen be started as adjunctive therapy (e.g. cyproterone acetate, 300 mg daily) about 5 days before starting treatment. This adjunctive therapy must be continued in parallel with buserelin therapy for 3 to 4 weeks. After this time testosterone levels have usually fallen into the desired range in response to buserelin.

Neurological sequelae have been reported where secondary deposits impinge upon the spinal cord or CNS. In patients with known metastases, e.g. of the spinal column, this adjunctive therapy with an anti-androgen is indispensable to prevent initial complications up to and including , for example, spinal compression and paralysis, arising from a transient activation of the tumour and its metastases (see section 4.8).

Published epidemiological studies suggest a relationship between gonadotrophin releasing hormone (GnRH) agonist treatment and increased risk of cardiovascular disease (such as myocardial infarction, sudden cardiac death, and stroke) and diabetes mellitus. These risks should be evaluated before initiating and during therapy, and patients should be monitored and treated accordingly.

Due to testosterone suppression, GnRH agonist therapy may increase the risk of anaemia. Patients should be evaluated for this risk and managed accordingly.

Once testosterone levels have started to fall below their baseline concentration clinical improvement should start to become apparent. If testosterone levels do not reach the therapeutic range within 4 weeks (6 weeks at the latest) the dose schedule should be checked to be sure that it is being followed exactly. It is unlikely that a patient who is taking the full dose will not show a suppression of testosterone to the therapeutic range. If this is the case, alternative therapy should be considered.

After the initial determination, testosterone levels should be monitored at 3-monthly intervals. A proportion of patients will have tumours that are not sensitive to hormone manipulation. Absence of clinical improvement in the face of adequate testosterone suppression is diagnostic of this condition, which will not benefit from further therapy with buserelin.

4.5    Interaction with other medicinal products and other forms of interaction

During treatment with Suprefact, the effect of antidiabetic agents may be attenuated (see section 4.8).

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Suprefact 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).

4.6    Pregnancy and lactation

Suprafact is contraindicated in pregnancy. It is intended for the treatment of advanced prostatic carcinoma, it should not be used in pregnant or lactating women (see 4.3 Contraindications).

Buserelin passed 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 Suprefact in order to prevent the infant from ingesting small quantities of buserelin with breast milk.

4.7. Effects on Ability to Drive and Use Machines

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

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 can occur. These may become manifest as 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.

Administration of the nasal spray, may irritate the mucosa in the nasopharynx. This may lead to nosebleeds and hoarseness as well as to disturbances of taste and smell.

At the beginning of treatment, a transient rise in the serum testosterone level usually develops and may lead to temporary activation of the tumour with secondary reactions such as:

-    occurence or exacerbation of bone pain in patients with metastases.

-    signs of neurological deficit due to tumour compression with eg. muscle weakness in the legs.

-    impaired micturition, hydronephrosis or lymphostasis.

-    thrombosis with pulmonary embolism.

Such reactions can be largely avoided when an anti-androgen is given concomitantly in the initial phase of buserelin treatment (see section 4.4 Precautions and Warnings). However, even with concomitant anti-androgen therapy, a mild but transient increase in tumour pain as well as a deterioration in general well-being may develop in some patients.

Suprefact 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 , sleep disturbances, tiredness, drowsiness. Occasional paraesthesia (especially in the arms or legs), disturbances of memory and concentration.

Eye disorders - Occasional dry eyes (possibly leading to eye irritations in people who wear contact lenses), impaired vision (eg 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 - Occasional gynaecomastia (increase in breast size) which is usually painless, atrophy of the testes, decrease in libido and potency (in most patients; result of hormone deprivation).

Most of the effects listed above are directly or indirectly related to the suppression of testosterone by buserelin (symptoms of androgen deficiency).

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, oedemas of the lower extremities, and mastodynia. Treatment should be symptomatic.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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 peptidases 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 stated

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Chloride Citric Acid Monohydrate Sodium Citrate Dihydrate Benzalkonium Chloride Water for Injections

6.2    Incompatibilities

Not applicable.

Shelf Life

2V years.

6.4    Special Precautions for Storage

Store below 25^oC. The spray solution should last for 1 week of treatment.

Any residual material after this time should be discarded.

6.5    Nature and Contents of Container

Box of 4 bottles each containing 10g solution and 4 spray pumps

6.6    Instructions for Use/Handling

How to use the spray bottle.

1.    Remove spray cap from bottle.

2.    Remove metered dose nebulizer from transparent plastic container and take off both protective caps.

3.    Screw nebuliser 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 the 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.

7    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

GUI 4YS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04425/0279

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 24 June 2002

10 DATE OF REVISION OF THE TEXT

19/02/2015