SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

HRF 500 microgram.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 micrograms of Gonadorelin as Gonadorelin Hydrochloride BP.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

HRF as a single injection is indicated for evaluating the functional capacity and response of the gonadotropes of the anterior pituitary. The LH/FSH-RH response is used in testing patients with suspected gonadotropin deficiency, whether due to the hypothalamus alone or in combination with anterior pituitary failure. HRF is also indicated for evaluating residual gonadotropic function of the pituitary following removal of a pituitary tumour or surgery and/or irradiation.

The HRF test complements the clinical assessment of patients with a variety of endocrine disorders involving the hypothalamic-pituitary axis. In cases where there is a normal response, it indicates the presence of functional pituitary gonadotropes. The single injection test does not determine the pathophysiological cause for the subnormal response and does not measure pituitary gonadotropic reserve.

4.2 Posology and method of administration

Route of administration

For subcutaneous and intravenous administration.

Adults and Elderly

100 micrograms, subcutaneously or intravenously. In females for whom the phase of the menstrual cycle can be established, the test should be performed in the early follicular phase (days 1-7).

Children

Do not use in children under one year as the diluent contains 2 % benzyl alcohol.

Test Methodology

To determine the status of the gonadotropin secretory capacity of the anterior pituitary, a test procedure requiring seven venous blood samples for LH/FSH-RH is recommended.

Procedure:

1.    Venous blood samples should be drawn at -15 minutes and immediately prior to HRF administration. The LH/FSH-RH baseline is obtained by averaging the LH/FSH-RH values of the two samples.

2.    Administer a bolus of HRF subcutaneously or intravenously.

3.    Draw venous blood samples at 15, 30, 45, 60 and 120 minutes after administration.

4.    Blood samples should be handled as recommended by the laboratory that will determine the LH/FSH-RH content. It must be emphasised that the reliability of the test is directly related to the inter-assay and intra-assay reliability of the laboratory performing the assay.

Interpretation of Test Results: Interpretation of the LH/FSH-RH response requires an understanding of the hypothalamic-pituitary physiology, knowledge of the clinical status of the individual patient, and familiarity with the normal ranges and the standards used in the laboratory performing the LH/FSH-RH assays.

Curves provided represent the LH/FSH-RH response curves after administration in normal subjects. The normal LH/FSH-RH response curves were established between the 10th percentile (B line) and 90th percentile (A line) of all LH/FSH-RH responses in normal subjects analysed from the results of clinical studies.

Individual patient responses should be plotted on the appropriate curve. A subnormal response in patients is defined as three or more LH/FSH-RH values which fall below the B line of the normal LH/FSH-RH response curve.

In cases where there is a blunted or borderline response, the HRF test should be repeated.

The HRF test complements the clinical assessment of patients with a variety of endocrine disorders involving the hypothalamic-pituitary axis. In cases where there is a normal response, it indicates the presence of functional pituitary gonadotropes. The single injection test does not determine the patho-

physiological cause for the subnormal response and does not measure pituitary gonadotropic reserve.

4.3 Contraindications

Hypersensitivity to HRF or any of its components. Known or suspected pregnancy. Do not use in children under one year of age as diluent contains 2% benzyl alcohol.

4.4 Special warnings and precautions for use

Although allergic and hypersensitivity reactions have been observed with other polypeptide hormones, to date no such reactions have been encountered following the administration of a single 100 micrograms dose of HRF used for diagnostic purposes. Rare instances of hypersensitivity reactions have been reported. Therefore, patients treated by intermittent pulsatile therapy in whom re-administration is considered, particularly by the intravenous route, should be carefully observed. Administration during the follicular phase of a normal cycle may result in premature ovulation and appropriate measures are advised to prevent an unwanted pregnancy in these circumstances.

4.5 Interaction with other medicinal products and other forms of interaction

The HRF test should be conducted in the absence of other drugs which directly affect the pituitary secretion of gonadotropins. These would include a variety of preparations which contain androgens, oestrogens, progestogens or glucocorticoids. The gonadotropin levels may be transiently elevated by spironolactone, minimally elevated by methyldopa, and suppressed by oral contraceptives and digoxin. The response to HRF may be blunted by phenothiazines and dopamine antagonists which cause a rise in prolactin.

4.6 Pregnancy and lactation

HRF should not be administered to pregnant women or nursing mothers.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Systemic complaints such as headache, nausea, light headedness, abdominal discomfort and flushing have been reported rarely following administration of HRF. Local swelling, occasionally with pain and pruritis at the injection site may occur if HRF is administered subcutaneously. Local and generalised skin rash have been noted after chronic subcutaneous administration.

Thrombophlebitis with septicaemia, mild and severe, has been reported in isolated cases at the site of intravenous injection. Rare instances of hypersensitivity reaction (bronchospasm, tachycardia, flushing, urticaria, swelling, itching and redness of the face, eyelids and lips, induration at injection site) have been reported following multiple-dose administration of large doses. Antibody formation has also been reported rarely after chronic administration of large doses.

4.9 Overdose

HRF has been administered parenterally in doses up to 3 mg bd for 28 days without any signs or symptoms of overdosage. In cases of overdosage or idiosyncrasy, symptomatic treatment should be administered as required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Gonadorelin stimulates the synthesis of follicle stimulating hormone and luteinising hormone in the anterior lobe of the pituitary as well as their release.

5.2 Pharmacokinetic properties

Gonadorelin is rapidly hydrolysed in plasma and excreted in urine with a half life of about 4 minutes.

5.3 Preclinical safety data

Not applicable.

6.1 List of excipients

Lactose monohydrate USP Solvent: Benzyl alcohol BP Water for injections BP.

6.2 Incompatibilities

HRF should not be mixed with any other substance.

6.3 Shelf life

Unopened: 48 months After reconstitution: 24 hours

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

HRF is supplied in a USP Type I clear glass vial with grey butyl rubber stopper and aluminium collar. The sterile solvent is 2 ml water for injections with 2% benzyl alcohol supplied in a Ph. Eur. Type I clear glass ampoule.

6.6 Special precautions for disposal

Preparation for single injection administration: Reconstitute 500 micrograms vial with 2.0 ml of the accompanying sterile solvent of 2 % benzyl alcohol. Prepare solution immediately before use. After reconstitution, refrigerate and use within 1 day. Discard unused reconstituted solution and solvent.

7    MARKETING AUTHORISATION HOLDER

Diamond Consultants Ltd 2 Wheeleys Road Edgbaston Birmingham West Midlands

United Kingdom B15 2LD

8    MARKETING AUTHORISATION NUMBER(S)

PL 41262/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/03/2011

10 DATE OF REVISION OF THE TEXT

27/12/2012