INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
HRF* Injection 0,1 mg
HRF* Injection 0,5 mg

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

HRF* Injection 0,1 mg
HRF* Injection 0,5 mg
Plus sterile diluent for HRF* Injection

COMPOSITION:
HRF is a sterile lyophilized powder for reconstitution and parenteral administration.

Powder for reconstitution: (per vial)
Synthetic luteinizing releasing hormone 0,1 mg or 0,5 mg.
Lactose 100,0 mg.

Sterile Diluent: (per ampoule)
Benzyl alcohol 2.0% as preservative.
Water for injection q.s. ad. 2 mL.

HRF is a synthetic decapeptide identical in structure to the natural porcine luteinizing hormone-releasing hormone isolated and identified by Schally and his co-workers at Tulane University.

PHARMACOLOGICAL CLASSIFICATION:
Category A, 21.10 Trophic hormones.

PHARMACOLOGICAL ACTION:
The administration of HRF, Wyeth/Ayerst’s synthetic LH/FSH releasing hormone, causes a significant secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from functional pituitary tissue.
This pharmacological activity is identical to the physiologic function of the endogenous LH/FSH-RH, which controls the release of antero-pituitary gonadotrophic hormone. (Under normal conditions, circulating oestrogen and progesterone levels influence, to a degree, the pituitary response by means of a feedback mechanism).
However, the releasing hormone itself is completely devoid of LH and FSH activity. It will not cause a rise in baseline levels of LH or FSH in the presence of a non-responsive pituitary, nor does it have any other demonstrable pharmacologic activity. Therefore, the secretion of these substances is dependent upon the presence of a normally active pituitary.
Because of its ability to provide a consistent release of LH and FSH, but to do this only via a functional pituitary, HRF CAN BE HIGHLY USEFUL AS A DIAGNOSTIC TOOL IN ASSESSING THE CAPABILITY OF THIS ENDOCRINE ORGAN and determining if the endocrinopathy with which a physician is confronted is related to pituitary, or to hypothalamic or peripheral gonadal dysfunction.

Distribution and metabolism:
A number of studies by Schally and others indicate that LH releasing hormone has a half-life of approximately four minutes, and probably breaks down rapidly into the basic amino acids. Investigations with titrated LH-RH disclosed a rapid disappearance of radioactivity from the circulation after intravenous injection.
The pineal gland, the anterior and posterior pituitaries, the kidney and liver, all showed a significant accumulation of radioactivity. Concentration of radioactivity by the two latter organs indicates that they are major sites for inactivation and excretion of the releasing hormone. By contrast, very little concentration of the substance was seen in the cerebral cortex, hypothalamus, or muscle tissue, and only a marginal accumulation of radioactivity was noted in the adrenal glands.

Experimental Pharmacology:
Biological studies have indicated that HRF is a very potent substance, active at a few nanograms in experimental animals. Investigations showed that the LH-releasing hormones:

1.	Provoked ovulation in both hamsters and rats after spontaneous ovulation was blocked by phenobarbital, fluphenazine, or pentobarbital and atropine. In rats, a single I.V. injection of HRF proved far more potent in reversing the antiovulatory effects of these substances than the isolated natural releasing hormone.
2.	Showed no evidence of LH activity, as evidenced by its failure to induce ovulation in hypophysectomized or pseudo-pregnant rats.
3.	Induced the secretion of no more than physiological amounts of LH and FSH, as evidenced by the fact that administration on the day of mating did not increase the number of implantations.
4.	Proved effective in reversing a persistent oestrus syndrome used as an experimental model of the Stein-Leventhal syndrome. Administration of HRF (1 µg/day) to rats in whom permanent oestrus had been established induced a return to regular cycling that lasted until sacrifice.
5.	Did not cause an oversecretion of gonadotropins (particularly FSH) as evidenced by the fact that periodic injections of high doses did not increase uterine and ovarian masses. Similar periodic high dosages in immature, prepubertal, or adult males had no effect on masses of androgen-dependent organs (ventral prostate, seminal vesicles, testes, and levator ani).
6.	Was effective at doses of 4,0 and 10,0 µg in advancing ovulation by 24 hours in dioestrus rats. It also proved active at 0,5 µg in provoking ovulation on the date of late proestrus in fluphenazine-treated rats, but inactive in oestrus, metoestrus or dioestrus animals.
7.	Caused the release of LH in rats treated with medroxyprogesterone acetate, inducing ovulation when the follicle maturation process was effected by pregnant mare serum.
8.	Caused the release of LH in rats treated with ethinyl oestradiol, inducing partial ovulation (66,7%) at a dose level of 2,5 µg when pregnant mare serum was given with the oestrogen.

INDICATIONS:
ALL CLINICAL WORK TO DATE HAS DEMONSTRATED UNEQUIVOCALLY THAT PARENTERAL ADMINISTRATION OF WYETH/AYERST LH/FSH-RH (HRF) TRIGGERS THE RELEASE OF MEASURABLE AMOUNTS OF PLASMA LH AND FSH IN THE PRESENCE OF A FUNCTIONING PITUITARY.
THUS IT PROVIDES AN ACCURATE AND DIRECT TEST OF PITUITARY CAPABILITY. THE DIAGNOSTIC USES ARE WIDESPREAD.

In testing the efficacy of HRF, the substance was administered to normal volunteers by all usual parenteral routes. Responses have been in exact accord with anticipated results, without a single failure.
The decapeptide also has been evaluated in a large number of cases where diagnosis of the endocrine dysfunction was previously established by other means. In all cases the findings obtained through HRF testing have been consistent with the predetermined diagnosis, or contributed to the further refinement of the diagnosis.
HRF has been utilized in evaluating pituitary function in a wide variety of male and female endocrinopathies. The following partial list comprises indications in which HRF has been used, or in which its application might be indicated. As the diagnostic uses of HRF expand, additional indications will be forthcoming.

In the Female:
Pituitary Tumours:
Acromegaly, Forbes Albright Syndrome, Cushing Syndrome, isolated Hypogonadotrophic Hypogonadism.

Pituitary Organic Lesions:
Sheehan Syndrome, Simmonds Syndrome.

Hypophysectomy or Pituitary Ablation, Hypothalamic Disorders:
Tumours, Organic lesions, Congenital lesions, (Kallmann Syndrome), Diabetes insipidus, Functional Disorders, Panhypopituitarism: Primary, Secondary (idiopathic or other).

Hypogonadotrophic Hypopituitarism, Primary Amenorrhoea:
Adult, Pubertal., Secondary Amenorrhoea without Galactorrhoea: Anorexia nervosa, Iatrogenic (contraceptives, antidepressants, other drugs, organic lesions), idiopathic, Psychogenic, Posttraumatism, Postpartum, Secondary Oligomenorrhoea with Galactorrhoea: Iatrogenic (contraceptives:, anti-depressants, other drugs, organic lesions) idiopathic, Non-postpartum-Argonzdel Castillo Syndrome, Postpartum-Chiari-Frommel Syndrome.

Other Syndromes:
Prader-Willi Syndrome, Stein-Leventhal Syndrome, Empty-sella Syndrome, Nelson Syndrome, Noonan Syndrome, Turner Syndrome.

In the Male:
Pituitary Tumours:
Acromegaly, Cushing Syndrome, isolated Hypogonadism, Hypopituitarism, (partial).

Pituitary Lesions:
Simmonds Syndrome, Endogenous and Exogenous.

Hypophysectomy or Pituitary Ablation:
Hypothalamic: Tumours, Traumatism, Congenital lesions (Kallmann Syndrome), Diabetes insipidus.

Functional Disorders, Panhypopituitarism:
Primary, Secondary (idiopathic or other).

Hypogonadotrophic Hypogonadism, Primary:
Adult, Pubertas, Cryptorchidism.

Secondary (with or without Oligospermia or Azoospermia):
Iatrogenic, Psychogenic, Systemic diseases, Traumatism, Idiopathic.

Other Syndromes: Frohlich, Klinefelter, Prader-Willi.

Female Infertility - Induction of Ovulation.
Anovulatory Cycles:
As with all cases of anovulatory infertility, it is recommended that the patient’s pituitary function be assessed together with an estimation of her potential for ovarian follicular maturation. If it is possible to undertake a programme of ovarian follicular maturation, monitored daily by serum or urinary oestrogen determination, a single dose of HRF should be administered intramuscularly, (200 µg to 500 µg) once adequate pre-ovulatory oestrogen levels have been reached.

When endocrine monitoring on a daily basis is not practical, an attempt should be made to ensure follicular maturation by appropriate means and to administer 200 µg HRF (I.M. or S.C.) on days 14, 15 and 16. This regimen may be repeated for 3 - 4 cycles or more.

Secondary Amenorrhoea:
After instituting an artificial cycle, give HRF one week in mid-cycle, in a dosage range of 200 - 500 µg daily I.M. or S.C. Repeat until normal cycle is re-established. Should endocrine monitoring show that early cycles are anovulatory, refer to schedule outlined above, under anovulatory cycles.

Note: In primary amenorrhoea, HRF therapy must be used in accordance with endocrinological principles, based on etiology, in each individual patient.

CONTRA-INDICATIONS:
To date, clinical experience has not shown any contraindications, or the need for particular precautions when the product is used as recommended.

DOSAGE AND DIRECTIONS FOR USE:
Wyeth/Ayerst hypothalamic releasing factor provides an accurate and direct test of pituitary function. The recommended dosage is as follows:

Routine Determination Method: 100 µg (single dose). Highly refined determination method: 25 - 500 µg (multiple dose).

Administration:
Intramuscular, intravenous, or subcutaneous injection and intravenous infusion.

1.	For a rapid and simple determination of pituitary response capability, a single 100 µg dose is suggested. Administration may be intramuscular, subcutaneous or intravenous injection, or by intravenous infusion.
2.	To obtain a determination of the threshold at which the pituitary is able to respond, an initial dose of 25 µg is recommended. This may be adjusted upwards as necessary, and doses as high as 500 µg have been used for this purpose. Administration may again be by any of the usual parenteral routes.

The optimum number of blood samples to be assayed for valid evaluation of pituitary function is five to six. These should be taken at baseline, and at 30, 60, 90, 120 and 180 minutes after administration of the releasing factor. For more precise evaluation, additional sampling may be indicated.

If measurement of possible changes in oestrogen or testosterone levels after administration of the releasing hormone is desired, such measurement may be performed on samples taken every two hours from two to twelve hours after administration.

SAMPLES SHOULD BE TAKEN AND TREATED IN ACCORDANCE WITH THE PROCEDURES OF THE LABORATORY WHERE THE ASSAYS ARE TO BE CARRIED OUT. For detailed information as to handling of blood samples, method of shipping, costs and similar data, the laboratory performing the assays should be consulted. It should be emphasized that the ultimate reliability of the test must be predicted upon the reliability of the laboratory performing the radio-immunoassay.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Safety Summary: The clinical studies have fully, confirmed the high degree of safety seen in the preclinical research. To date no investigator has reported any adverse reactions or untoward effects of any type.

Tolerance of the substance has been excellent, even when it was administered daily for as long as 10 days at doses far beyond the recommended diagnostic level. No allergic phenomena or hypersensitivity reactions. and no apparent contra-indications or necessary precautions have been found.

Information about the safety of HRF, obtained by detailed testing in rats and monkeys, may be summarized as follows:

1.	Even when administered experimentally at levels as high as 50 times the recommended clinical dosage, it was impossible to achieve an LD-50.
2.	A complete lack of toxicity in experimental animals was seen regardless of whether the drug was administered by intramuscular, subcutaneous, or intravenous injection, or by intravenous infusion.
3.	It had virtually no effect on blood pressure, ECG, or heart or respiratory rate in experimental animals, nor could any effect be seen on general behaviour, body organs, or a wide variety of haematology, urine, and other clinical chemistry parameters.
4.	It had no teratogenic or embryopathic effect, and no effect upon reproductive capacity.
5.	The liver and kidneys are apparently the major sites for inactivation and excretion of the compound.

CONDITIONS OF REGISTRATION:
May be advertised to the professions only.

IDENTIFICATION:
HRF is a white lyophilized powder.

PRESENTATION:
Each package provides one vial containing 100 µg or 500 µg synthetic luteinizing releasing hormone in dry form and one 2 mL ampoule sterile diluent.

STORAGE INSTRUCTIONS:
The lyophilized cake is stable for three years at room temperature and the reconstituted cake is stable for one month at room temperature.
The product may be stored at room temperature (25 °C).
Keep out of the reach of children.

REGISTRATION NUMBERS:
HRF 0,1 mg - G/21.10/53
HRF 0,5 mg - G/21.10/70

REFERENCE NUMBER:
Sterile Diluent for HRF Injection - G3254 (Act 101/1965)

NAME AND BUSINESS ADDRESS OF APPLICANT:
AKROMED PRODUCTS (PTY) LTD.
Electron Avenue, ISANDO, 1600

Trademark and product, under licence from
WYETH-AYERST LABORATORIES, U.S.A.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
8 June 1978
        485-9043
        Davbar Dbn.
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