Suprefact Nasal Spray Buserelin acetate. Each bottle of 10 g ...

SUMMARY OF THE PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Suprefact Nasal Spray
1.1 Active ingredient
Buserelin acetate.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each bottle of 10 g aqueous solution contains, as active ingredient, 10.5 mg buserelin
acetate, equivalent to 10 mg buserelin. Each spray dose (100 mg) contains 0.105 mg
buserelin acetate, equivalent to 0.1 mg buserelin. Excipients: Benzalkonium chloride
(preservative), citric acid, sodium chloride, sodium citrate, water for injections.
3 PHARMACEUTICAL FORM
1 metered dose nebuliser.
4 CLINICAL PARTICULARS
4.1 Therapeutic Indications
Treatment of advanced hormone-dependent prostatic carcinoma.
Endometriosis, unless the disease primarily requires surgical treatment.
Pituitary desensitization in preparation of ovulation induction, as an adjunct to
gonadotrophin administration.
Polycystic Ovarian Disease (PCOD), Leyomyoma Uteri, Precocious Puberty.
4.2 Posology and method of administration
To ensure the desired effect it is very important that individual doses be administered
at approximately equal intervals. Patients must adhere to these intervals
conscientiously.
Prostatic carcinoma
Superfact nasal is intended for maintenance therapy. Following the initial 7-day
treatment with Superfac injectable, therapy continues on the eighth day with Superfact
nasal.
The daily intra nasal dose is 1.2 mg buserelin, irrespective of body weight. One spray
dose is administered in each nostril 6 times daily, according to the following schedule:

Left nostril right nostril
1 st dose before breakfast 1x 1x
2nd dose after breakfast 1x 1x
3rd dose before midday meal 1x 1x
4th dose after midday meal 1x 1x
5th dose before evening meal 1x 1x
6th dose after evening meal 1x 1x
Adjunctive therapy : About five days before the initiation with Suprefact injectable, an
antiandrogen (e.g. cyproterone acetate, flutamide or nilutamide) should be
administered at the manufacturer's recommended dosage, and administration then
continued concomitantly over three to four weeks (see under "Special warnings and
precautions" and Adverse effects").
The response to treatment may be monitored by measuring levels of testosterone, acid
phosphatase and prostate-specific antigen (PSA) in serum. Testosterone concentration
increases at the start of treatment and then decreases over a period of 2 weeks,
reaching the castrate range after two to four weeks and remaining at this level for the
duration of treatment. The duration of treatment is determined by the doctor.
Endometriosis :
The daily dose of buserelin is 0.9 mg (equivalent to 9 spray doses of 0.1 mg each),
regardless of body weight.
The usual duration of treatment is six months. It should not be exceeded. Omly a
single course of treatment is recommended.
Adjunctive use in ovulation induction:
The initial daily dose of Buserelin is 0.6 mg (equivalent to 6 spray doses of 0.1 mg
each), spread over the waking hours. For some patients it may be necessary to
increase the daily dose to up to 1.2 mg (equivalent to 12 spray doses of 0.1 mg each).
Treatment should start in the early follicular phase (day 1) or - provided that early
pregnancy has been excluded (a pregnancy test is recommended if there is any doubt)

- the mid-luteal phase (approx. day 21) of the cycle. Buserelin should be discontinued
on the first day of administration of human chorionic gonadotrophin. Ovarian
stimulation with gonadotrophins should only be started after a sufficient reduction in
oestradiol release has been achieved. This takes 2 or 3 weeks in most patients.
The spray doses are administered in each nostril according to the dosage schedules.
The therapeutic effect of Superfact nasal can be achieved if the dosage is
conscientiously adhered to. It is, therefore, advisable to administer Superfact nasal
before and after meals. It may also be used at other times provided uniform intervals
are maintained between doses.
For technical reasons a small amount of excess solution will remain in the bottle.
Special notes
If the spray is used correctly, reliable of the active ingredient takes place via the nasal
mucous membrane. Buserelin is absorbed even if the patient has a cold. However, the
nose should be blown vigorously before administration in such cases.
4.3 Contraindications
Hypersensitivity to buserelin or any of the excipients.
After surgical removal of the testes, no further reduction of testosterone levels by
Superfact nasal can be expected.
Buserelin must not be used in pregnancy.
Buserelin passes into breast milk in small amounts. Although negative effects on the
infant have not been observed, breast-feeding should be avoided during treatment of
endometriosis with Buserelin to prevent the infant from ingesting buserelin with
breast milk.
Undiagnosed vaginal bleeding, hypersensitivity to LHRH hormone dependant
neoplasms.
4.4 Special warnings and special precautions for use
In hypertensive patients, blood pressure must be monitored regularly (risk of increase
in blood pressure).
In diabetic patients, blood sugar levels must be checked regularly (risk of
deterioration of metabolic control).
Patients with a history of depression must be monitored carefully and, if necessary,
treated (risk of recurrence or worsening of depression).

Prostatic carcinoma
It is strongly recommended that administration of an antiandrogen be started as
adjunctive therapy about 5 days before starting treatment.
This therapy must be continued concomitantly with buserelin therapy for 3 to 4 weeks
(see under "Dosage and administration"). After this time, testosterone levels have
usually fallen to within the desired range.
In patients with known metastases (e.g. of the spinal column), this adjunctive therapy
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 also under "Adverse effects").
After the initial determination, testosterone levels should be monitored at 3-monthly
intervals. 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 as the latest) the
dose schedule should be checked to be sure that it is being followed exactly. 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 therapy with
buserelin.
Endometriosis:
Use of oral contraceptives must be discontinued before treatment is started. For
reasons of safety, once treatment has begun, alternative, non- hormonal contraception
methods (e.g. condoms) should be substituted in their place.
To exclude pre-existing pregnancy at the start of therapy, treatment should begin on
the first or second day of menstruation. If there is in any doubt, a pregnancy test is
recommended.
In the later stages of treatment, it is unlikely that pregnancy will occur if the
recommended doses are administered regularly. However, if treatment is interrupted,
even for only a few days, ovulation and pregnancy may occur.
If pregnancy does occur, treatment must be discontinued immediately and a physician
informed.
Since a reduction in bone mass cannot be ruled out, the attending physician must
conduct a careful risk-benefit assessment before repeated courses of therapy.
Adjunctive use in ovulation induction;
A pregnancy test should be performed before treatment is started.
In in-vitro fertilization, induction of ovulation must be performed under close medical
supervision.

When gonadotrophins are used together with Buserelin, the risk of ovarian
hyperstimulation syndrome is higher than with use of gonadotrophins alone.
Possible clinical signs of this syndrome 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, oliguria,
haemoconcentration, hypercoagulability. Pedicle torsion or rupture of the ovary may
lead to an acute abdomen. Severe thromboembolic events may also occur. Ovarian
hyperstimulation syndrome can be fatal.
Each stimulation cycle must be monitored carefully to permit early identification of
affected patients. It may necessary to omit treatment with human chorionic
gonadotrophin (hCG).
4.5 Effects on ability to drive and use machines
Certain adverse effects (e.g. dizziness) may impair the ability to concentrate and react,
and, therefore, constitute a risk in situations where these abilities are of particular
importance (e.g. operating a vehicle or machinery).
4.6 Interaction with other medicinal products and other forms of interaction
During treatment with buserelin, the effect of antidiabetic agents may be attenuated
(see also under "Adverse effects").
If nasal decongestants are being used concurrently, they should be administered at
least 30 minutes after buserelin.
Endometriosis:
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.
4.7 Undesirable effects
Prostatic carcinoma
At the start of treatment, a transient rise in the serum testosterone levels usually
develops and may lead to a temporary activation of the tumour with secondary
reactions such as:
- Occurrence or worsening of bone pain in patients with bone metastases.
- Signs of neurologic deficit due to tumour compression with e.g. muscle
weakness in the legs.
- Impaired micturition, hydronephrosis or Iymphostasis.
- Thrombosis with pulmonary embolism.
Such reactions can be largely avoided when antiandrogen is given concomitantly in
the initial phase of buserelin treatment (see also under "Special warnings and
precautions").

Even then, however, a mild but transient increase in tumour pain as well as a
deterioration in general well- being may develop in some patients.
Additionally, as a result of hormone deprivation, hot flushes and loss of potency or
libido occur in most patients. Mild oedemas of the ankles and lower leg may occur as
may, occasionally, usually painless gynaecomastia.
Endometriosis and Preparation of ovulation induction:
Treatment with Buserelin inhibits oestrogen production. In addition to the intended
therapeutic effects, this may lead also to adverse effects (dose-dependent); i.e., where
buserelin for preparation for ovulation induction is used at low dosage, these effects
occur less frequently and are less pronounced that in the treatment of endometriosis.
Uterine bleeding ("period"), as a manifestation of inhibited oestrogen production,
occurs in most patients, usually in the first weeks of treatment. Occasionally,
however, it may occur in the later stages of treatment.
Recovery of pituitary-gonadal function usually occurs within 8 weeks of
discontinuing treatment. In addition, menopausal-like symptoms, such as hot flushes,
increased sweating, vaginal dryness, pain during sexual intercourse, decreased libido,
and (may be severe in some patients) after several months' treatment - a decrease in
bone mass, may occur.
Further adverse effects not clearly attributable to hormone deprivation are: increase or
decrease in breast size (with breast tenderness), splitting nails, acne, dry skin;
occasionally, vaginal discharge and oedema on the face and extremities may also
occur.
In addition, lactation, pain in the stomach or lower abdomen, abnormal sensations
(especially in the arms or legs) may occur, as may dryness of the eyes (possibly
leading to eye irritation in patients who wear contact lenses).
Endometriosis:
Ovarian cysts may develop in the initial phase of treatment.
Preparation of ovulation induction:
In-vitro fertilization/embryo transfer programs and similar assisted reproduction
procedures carry inherent risks, e.g. increased occurrence of ectopic pregnancies,
miscarriages or multiple pregnancies. These risks are also present when 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.
In the initial phase of treatment with Buserelin, ovarian cyst may develop; however,
no negative effects on the course of stimulation has been reported so far.

Combined use with gonadotrophins may carry a higher risk of ovarian
hyperstimulation syndrome (OHSS) than the use of gonadotropins alone (see also
under "Special warnings and precautions").
Applies to all indications:
Very rare cases of pituitary adenomas were reported during treatment with LHRH
agonists including buserelin.
Buserelin treatment may lead to:
- increase or decrease in scalp or body hair.
- increase in blood pressure in hypertensive patients.
- hypersensitivity reactions. These may become manifest as, e.g. reddening of
the skin, itching, skin rashes (including urticaria) and allergic asthma with
dyspnoea but may also, in isolated cases, lead to anaphylactic/anaphylactoid
shock.
- reduction in glucose tolerance (possible deterioration of metabolic control in
diabetic patients).
- changes in blood lipids; increase in serum levels of liver enzymes (e.g.
transaminases) or in bilirubin; thrombopenia and leucopenia.
- headaches in up to 10% of patients receiving buserelin. These tend to occur at
the start of treatment and are seldom severe enough to necessitate the
discontinuation of buserelin therapy, palpitations, nervousness, sleep
disturbances, tiredness, drowsiness, disturbances of memory and
concentration, emotional instability, feelings of anxiety. In rare cases,
depression may develop or existing depression may worsen.
- dizziness, tinnitus, hearing disorders, impaired vision (e.g. blurred vision),
feeling of pressure behind the eyes.
- nausea, vomiting, increased thirst, diarrhoea, constipation, changes in appetite,
weight changes (increase or decrease).
- musculoskeletal discomfort and pain (including shoulder pain/stiffness in
women). 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.
- irritation of the mucosae of the nasal and pharyngeal cavity; this may lead to
nosebleeds, hoarseness or disturbances of smell and taste.
4.8 Emergency measures to be taken in the event of anaphylactic shock
Generally, the following emergency procedure is recommended: At the first signs
(sweating, nausea, cyanosis), perform venous cannulation. In addition to the usual
emergency measures, ensure that the patient remains lying down, with the legs raised
and airways patent.
Emergency drug therapy:
Immediately epinephrine (adrenaline) i.v.: In the first instance, slowly inject 1 ml of a
solution containing 0.1 mg epinephrine per ml while monitoring pulse and blood
pressure (watch for disturbances in cardiac rhythm). Repeat as required. Then volume

substitution i.v., e.g. plasma expanders, human albumin, balanced electrolyte solution.
Subsequently glucocorticoids i. v., e.g. 250 - 1000 mg methylprednisolone. Repeat as
required.
The dosage recommendations refer to adults of normal weight. In children, the
reduction of dose should be in relation to body weight. Other therapeutic measures,
e.g. artificial respiration, oxygen inhalation, antihistaminics.
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.
Therapy for overdose is directed to the symptoms.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Buserelin is an analogue of the natural gonadotrophin-releasing hormone
(gonadorelin; GnRH) with enhanced biological activity. After repeated administration
of buserelin, the secretion of gonadotrophins and gonadal steroids is significantly
inhibited.
The pharmacological effect is attributable to the down-regulation of pituitary LH-RH
receptors.
In male individuals the elimination of gonadotrophin release results in a lasting
reduction in the synthesis and secretion of testosterone. In female individuals the
elimination of pulsatile gonadotrophin release reliably inhibits the secretion of
oestrogen.
The suppressive effect of buserelin on the secretion of gonadal steroids depends on
the daily dose, the frequency of application and the duration of treatment.
Even when the serum level of buserelin is below the detection limit, gonadotrophin
release is preserved because of sustained binding to the receptors of the anterior lobe
of the pituitary gland (approx. 3 hours).
While gonadotrophin release is inhibited during long-term treatment with buserelin,
the secretion of the other pituitary hormones (growth hormone, prolactin, ACTH,
TSH) is not directly influenced. However, oestrogen deficiency may lead to decreased
secretion of growth hormone and prolactin. The secretion of adrenal steroids remains
unchanged.
Applies only to the indication "prostatic carcinoma":
In terms of the complete inhibition of testicular testosterone synthesis, buserelin is
equally as effective as orchiectomy in the treatment of prostatic carcinoma. Compared
with orchiectomy, buserelin offers the advantage of reversibility and reduced
psychological stress for the patient.

6 PHARMACEUTICAL PARTICULARS
Buserelin is water-soluble; when administered by subcutaneous injection it is reliably
absorbed.
If administered correctly by the nasal route, it is absorbed via the nasal mucosa in
such a way that sufficiently high plasma levels are guaranteed. The biological activity
of buserelin was not impaired even after the induction of histamine rhinitis in test
subjects.
The nasal absorption of buserelin from buserelin nasal solution is 1 to 3%. After
subcutaneous injection of 200 µg, buserelin is 70% bioavailable; in contrast, after oral
administration, buserelin is ineffective.
Buserelin accumulates preferentially in the liver and kidneys as well as in the anterior
pituitary lobe, the biological target organ.
The elimination half-life is approx. 50 to 80 minutes following intravenous
administration, 80 minutes after subcutaneous administration and approx. 1 to 2 hours
after intranasal administration.
Buserelin circulates in serum predominantly in intact, active form. Protein binding is
approx. 15%. Buserelin and inactive buserelin metabolites are excreted via the renal
and the biliary route. The serum concentration and the excretion of buserelin in the
urine show the same time profile. In man, approx. 50% of buserelin excreted in the
urine is intact.
Buserelin is metabolized by peptidases (pyroglutamyl peptidase and chymotrypsinlike
endopeptidases) in the liver and kidneys as well as in the gastrointestinal tract and
by this means inactivated. In the pituitary gland, receptor-bound buserelin is
inactivated by membrane-located enzymes.
A small proportion of the dose of buserelin is secreted into the breast milk. According
to present clinical experience these amounts have no hormonal effect on the infant.
6.1 Non-Clinical Safety Data
No signs of toxicity or histopathological changes were detected in long-term
pharmacology and toxicology studies in rats, dogs and monkeys; the endocrine effects
observed were restricted to the gonads.
Pituitary adenoma occurs during long-term treatment in rats; this phenomenon has not
been found in dogs and monkeys.
• Reproduction toxicology
Buserelin has no embryotoxic or teratogenic effects. No maternal toxicity or fetotoxic
effects relevant to humans have been observed in any animal studies.
• Immunotoxicology
In animals and humans there was no antibody formation to buserelin, even during
long-term treatment.
• Mutagenicity
Buserelin showed no mutagenic potential in any of the studies performed.
• Neoplastic potential
Buserelin showed no carcinogenic potential in any of the studies performed.
• Local tolerance
The local tolerance of buserelin after injection or after application to mucosa in
aqueous solutions is excellent. The local tolerance of buserelin implants is good, and
tissue reactions at the injection site are minor.

6.2 Special precautions for storage
Store between +2° and +25°C. Do not allow to freeze.
Once opened, the bottles may be stored at room temperature.
Keep medicines out of the reach of children.
6.3 Instructions for use and handling, and disposal (if appropriate)
This preparation will only be effective if the instructions for use in this leaflet are
followed carefully.
1. Remove screw cap from bottle.
2. Remove metered-dose nebulizer from plastic container and take off both
protective caps - one white, the other transparent.
3. Screw nebulizer onto bottle.
4. Before first application only, holding bottle upright, work pump vigorously
about 10 times to fill the system with solution and guarantee emission of a
uniform spray.
5. Keeping bottle upright and bending head slightly forwards, spray solution into
nostril. If necessary, blow nose before administering the solution.
6. Always keep nebulizer screwed on bottle. Replace protective cap after each
use.
Please note: To avoid wasting bottle contents, perform preliminary pumping
prior to first application only.
Manufacturer: Aventis Pharma, Germany.
Importer: Aventis Pharma Ltd. 1 Haomanut st. P.O.B. 8090, Netanya 42170, Israel.
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