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Logo SUPREFACT® i (Injectable)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

SUPREFACT® i (Injectable)

COMPOSITION:
Each 1 mL of the aqueous solution contains 1,05 mg
buserelin acetate corresponding to 1 mg buserelin base as the active ingredient.
As preservative: Benzyl alcohol 1,0% m/m.

PHARMACOLOGICAL CLASSIFICATION:
Category A: 21.10: Trophic hormones.

PHARMACOLOGICAL ACTION:
Suprefact contains buserelin, an analogue of the natural gonadorelin (GnRH, HLH-RH) with a long duration of action.
Gonadorelin stimulates both synthesis and release of the gonadotropins LH and FSH. The latter then stimulates steroid biosynthesis in the gonads. Studies of the behaviour of the receptor sites, both of gonadal LH-receptors and pituitary GnRH-receptors have shown that long-term stimulation leads at first to an increase but then to a reduction in the stimulability of both gonadotropins and sexual steroid levels. The dose-level and time interval between individual doses of GnRH are determinant factors for the receptor loss as indicated in animal studies.
The suppressive effect is fully reversible. Genuine gonadorelin is bound to receptors for only a short time. It is degraded within 30 to 60 minutes by arylamidase and its activity thus abolished. For therapeutic use the highly-potent, therefore long-active analogue buserelin, has been developed. Enzymic degradation is inhibited by substitution of the amino acid, glycine, at two sites in the molecule.
Buserelin is thus bound to the receptors for a longer time and is effective for more than three hours.
Its elimination half-life from serum does not differ significantly from that of gonadorelin.
Buserelin produces much greater receptor-loss than gonadorelin.
At adequate dose-levels, administration three times daily is sufficient. Suprefact is capable of inhibiting both gonadotropin release, from the pituitary and gonadal steroid-biosynthesis and is thus indicated for the treatment of hormone-dependent tumours such as prostatic carcinoma. Of particular importance is the complete reversibility of the suppressive effect, thus permitting temporal control of the pituitary-gonad-axis.

INDICATIONS:
Prostatic carcinoma in which suppression of testosterone production is indicated.

CONTRA-INDICATIONS:
Suprefact should not be used if the tumour is found to be insensitive to the medicine, after surgical removal of the testes, or after treatment with oestrogen therapy.
Should not be used in patients who are hypersensitive to benzyl alcohol or to buserelin acetate.

DOSAGE AND DIRECTIONS FOR USE:
Introduction of suppressive therapy: The patient should be admitted to hospital and 0,5 mL Suprefact i (for injection) injected sub-cutaneously 3 times a day at 8 hourly intervals, for a period of 7 days. This dose is equivalent to 1,5 mg buserelin daily and is independent of body mass.

Continuation of suppressive therapy: On the 8th day of treatment, the regimen of treatment is changed from the previously given subcutaneous form to the Suprefact ns Nasal Spray and the duration of treatment is determined by the doctor.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
At the start of treatment with Suprefact there is a temporary rise in sex hormones, which usually remains within the normal range. In a few patients this rise may be associated with an increase in the symptoms of the disease, such as bone pain, impaired micturition, muscular weakness in the legs as manifestation of temporary activation of the tumour. These symptoms usually subside spontaneously without necessitating withdrawal of Suprefact.
According to present information, however, they can be avoided by additionally prescribing an antiandrogen (e.g. cyproterone acetate, flutamide) at the start of treatment. It is therefore advisable in patients in whom temporary increase in size of tumour may lead to urinal tract obstruction, paresis due to increased pressure on the spinal cord, or increased intracranial pressure (in rare cases with brain metastases) to administer an antiandrogen about five days before the start of Suprefact treatment and continue it for three to four weeks in conjunction with the Suprefact therapy until the sex hormones have fallen to a satisfactory level.
Owing to the suppression of sex hormone synthesis, hot flushes are to be expected in the majority of cases and loss of potency and libido occur in all cases. Also as a result of the suppression of sex hormones, breast enlargement and depressive moods may rarely occur. Patients with a known history of depression should be monitored carefully.
Infrequently, hypersensitivity reactions to buserelin or benzyl alcohol may occur, such as reddening of the skin and urticaria-like skin changes and exanthema.
Allergic (anaphylactic) shock is rare, but acutely life-threatening if it does occur (for recommended measures, see below).
Other side effects reported include thrombosis with pulmonary embolism, nausea, vomiting, diarrhoea, dizziness and transient headache.
Subcutaneous treatment with Suprefact i injection is regarded as a pre-treatment, which is replaced on the 8th day by an intranasal spray.
No serum testosterone tests are carried out during the first week of treatment. Instructions for the tests recommended during long-term treatment are given in the package insert of the special dosage form, Suprefact ns Nasal Spray.
Monitoring of the clinical effect of Suprefact i injection is carried out by the methods generally used in prostatic carcinoma. As the testosterone level in the serum does not fall immediately after the start of treatment, the onset of the clinical effect may also be delayed.
There are no known interactions between buserelin and any other concomitant medication.
At the start of the treatment with Suprefact, a transient activation of the tumour may occur. In the rare instances, symptoms of neurological disorders (e.g. muscular weakness in the legs) may develop, which in isolated cases are serious.

Emergency measures to be taken in the event of anaphylactic shock:
The following emergency measures are generally recommended: At the first signs (sweating, nausea, cyanosis) interrupt the injection immediately and perform venous cannulation.
In addition to the usual emergency measures, ensure that the patient is kept flat with the legs raised and airways patent. Emergency drug therapy:
Immediately epinephrine (adrenaline) i.v.: Dilute 1 mL of commercially available epinephrine solution 1:1°000 to 10 mL. In the first instance slowly inject 1 mL of this dilution (equivalent to 0,1 mg epinephrine) while monitoring pulse and blood pressure (watch for disturbances of cardiac rhythm). The administration of epinephrine may be repeated. Then glucocorticoids i.v., e.g. 250 -1000 mg methylprednisolone. The glucocorticoid administration may be repeated.
Subsequently volume substitution i.v., e.g. plasma expanders, human albumin, balanced electrolyte solution.
Other therapeutic measures: Artificial respiration, oxygen inhalation, antihistaminics.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
There are no known symptoms of over-dosage.

IDENTIFICATION:
A clear, colourless to pale yellowish solution in a multidose vial of 5,5 mL

PRESENTATION:
Packs of two 5,5 mL multidose vials.

STORAGE INSTRUCTIONS:
Store between 2°C and 25°C.
Do not freeze.
Keep out of reach of children.
The date of first withdrawal should be noted down on the label. Once opened, the vials should be stored at 25°C and for not longer than 2 weeks.

REGISTRATION NUMBER:
V/21.10/169

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
NORISTAN LIMITED
326 Marks Street, Waltloo, Pretoria

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
January 1988.

HOECHST Pharmaceuticals, Division of
NORISTAN LIMITED
WALTLOO, PRETORIA

PHSX - G43 - 0037

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