Relefact TRH (Protirelin)

RELEFACT® TRH

Hoechst Marion Roussel

Protirelin

Synthetic Thyrotropin Releasing Hormone

Action And Clinical Pharmacology: Protirelin stimulates the secretion of pituitary thyroid stimulating hormone (TSH). This effect may be used clinically to assess the functional integrity of the hypothalamic-pituitary-thyroid axis by estimating TSH concentrations in the peripheral plasma.

In addition to its stimulatory effect on secretion of pituitary TSH, it has been shown that protirelin increases secretion of prolactin.

Approximately 65% of acromegalic patients, tested with TRH, respond with a rise in circulating Human Growth Hormone (HGH) levels; the clinical significance of this is as yet not clear. It is possible that synthetic TRH testing may result in increases of circulating HGH levels in other pathophysiologic states, including renal failure, hepatic disease, hypothyroidism, anorexia nervosa, or mental depression.

TSH response, following i.v. administration of synthetic TRH, may be blunted in some patients with mental depression; an association between hypothyroidism and clinical depression is claimed by several sources.

A proportion of patients with Cushing’s syndrome, tested with synthetic TRH, respond with a blunted, or absent, rise in TSH and a concomitant rise in Adrenocorticotropic Hormone (ACTH).

The possibility that protirelin testing may affect other hormonal systems in certain pathophysiologic states cannot be excluded.

Studies in human euthyroid subjects have shown that i.v. injections of synthetic TRH, in doses ranging from 25 to 800 µg, produce an elevation of plasma TSH. Peak levels were observed between 10 and 30 minutes following injection.

Upon synthetic TRH administration, patients with hyperthyroidism, primary hypothyroidism, or hypopituitarism show various TSH secretion patterns differing from that obtained with euthyroid subjects.

Interpretation of the response of patients to protirelin injection is based on the increase of plasma levels of TSH. The changes observed in various conditions following protirelin administration are briefly outlined below. (Thyroxine (T4), liothyronine (T3), and plasma protein bound-iodine (PBI) levels may also show increases from baseline values). Hyperthyroidism: no rise in serum TSH; euthyroid Graves Disease: blunted or no TSH response; primary hypothyroidism: exaggerated and prolonged elevation in TSH levels; hypopituitarism: a deficiency in TSH secretion may be observed after stimulation with protirelin, in which case the TSH response is blunted or absent.

When 5 different doses of synthetic TRH, ranging from 10 to 800 µg, were administered i.v. to healthy male and female adult subjects, TSH and prolactin levels were significantly affected. The male subgroup showed a dose-related response at doses ranging from 10 to 400 µg with no further increase in levels of serum TSH at a dose of 800 µg. The female subgroup showed a significant increase in serum level of TSH at the 25 µg dose when compared to the 10 µg dose; however, no significant difference took place in serum TSH levels at the four highest doses (25 to 800 µg) of synthetic TRH injection.

From the data outlined above, and using the T3-TRH bioassay, the plasma half-life was calculated to be approximately 5 minutes. In the same tests, clearance was calculated to be 140 mL/min.

Indications And Clinical Uses: May be used as a diagnostic test for the evaluation of the hypothalamic-pituitary-thyroid axis.

Contra-Indications: Known hypersensitivity to protirelin.

Pregnancy: Until further evidence of a lack of drug-induced fetal abnormalities becomes available, protirelin should not be used in pregnant patients.

Protirelin should not be administered to patients in whom marked, rapid changes in blood pressure would be dangerous.

Manufacturers’ Warnings In Clinical States: Pregnancy: Since the teratogenic properties of synthetic TRH have not been established in women of childbearing potential, perform the test during the first 10 days following the onset of menstruation or when pregnancy is ruled out.

No studies have been conducted in human pregnancy which would relate to fetal safety of protirelin. Animal reproduction studies, performed in rats and rabbits with doses 1 1/2 and 6 times the human dose, have shown an increase in the number of resorption sites in the pregnant rabbit.

Due to an effect on smooth muscle contraction, protirelin should be administered with caution to patients with cardiac disease, hypertension, labile blood pressure, renal insufficiency or bronchial asthma.

Upon i.v. protirelin administration, transient changes (increases, decreases) in blood pressure have been observed. Therefore, blood pressure should be measured before protirelin is administered and at frequent intervals during the first 15 minutes after its administration. Increases in systolic blood pressure (usually less than 30 mm Hg) and/or increases in diastolic blood pressure (usually less than 20 mm Hg) have been observed more frequently than decreases in blood pressure. These changes have not ordinarily persisted for more than 15 minutes, nor have they routinely necessitated corrective therapy.

More severe degrees of hypertension or hypotension (with or without syncope) have been reported in a few patients. Hypotensive episodes have involved administration of synthetic TRH alone, and combinations of (synthetic) TRH and insulin with/without luteinizing hormone releasing hormone (LHRH/GnRH). Symptoms also included decreased cardiac output, absent pulses, and apnea. Patients recovered, some experiencing transient bradycardia during recovery.

To minimize the incidence and/or severity of hypotension the patient should be supine before, during and for at least 15 minutes after administration of Relefact TRH. This is particularly important for persons with labile blood pressure, documented hypertension and older persons with compromised cardiovascular function.

If a clinically important change in blood pressure occurs, monitoring of blood pressure should be continued until it returns to baseline levels.

Pituitary apoplexy requiring acute neurosurgical intervention has been reported in patients with pituitary adenomas following the administration of protirelin injection in combination with LHRH/GnRH and insulin.

Severe headaches, with and without temporary amaurosis, have been reported in patients with pituitary tumors given TRH in combination with LHRH/GnRH. Patients rechallenged with LHRH/GnRH did not experience event recurrence; rechallenge with TRH resulted in recurrence of symptoms.

Convulsions or seizures, with and without unconsciousness, have been reported in patients with predisposing conditions of epilepsy, brain lesion, pituitary tumor, or head injury, following administration of TRH or the combination TRH with LHRH/GnRH.

Precautions: Failure of response to synthetic TRH in some euthyroid patients has been reported. Consequently, protirelin testing is most valuable when used in conjunction with other diagnostic aids.

Protirelin is a peptide, and must therefore be regarded as potentially allergenic.

The protirelin diagnostic test should not be repeated in the same individual within 7 days because frequent administration may lead to erroneous test results.

Thyroid hormones reduce the TSH response to protirelin. Accordingly, patients to whom protirelin is to be administered (for diagnostic testing) should be taken off liothyronine (T3) approximately 7 days prior to testing, and should be taken off thyroid medications containing levothyroxine (T4) at least 14 days prior to testing. Thyroid hormone therapy is not to be discontinued when the protirelin test is employed to evaluate the effectiveness of thyroid suppression with a particular dose of T4 in patients with nodular or diffuse goitre, or when the TRH test is administered to adjust dosage of thyroid hormone given to patients with primary hypothyroidism.

Drug Interactions: Generally, the withdrawal of adrenocorticoids, administered in the therapy of known hypopituitarism, is not recommended. Pharmacologic doses of glucocorticoids reduce the TSH response to protirelin, but physiologic doses do not appear to have a significant effect on this response.

The diagnostic use of dexamethasone has been shown to reduce TSH response to TRH testing; ethynylestradiol has been shown to cause a rise in serum levels of TSH.

Caffeine and theophylline may enhance the activity of TRH; hence, patients should avoid beverages containing these substances 12 to 14 hours before administration of protirelin.

Administration of levodopa (L-Dopa) has been reported to reduce the TSH response to synthetic TRH.

The ingestion of ASA caused the peak level of TSH to decrease approximately 30% as compared to values obtained without ASA administration. In both cases, the TSH peak occurred 30 minutes postadministration of protirelin.

Other pharmacologic/hormonal agents which may depress the TSH response to TRH include dopamine, bromocriptine, chlorpromazine, thioridazine, phentolamine, cyproheptadine, methysergide, or somatostatin.

Adverse Reactions: Generally, side effects have been of a minor nature, with prompt onset and persistence for a few minutes following injection of protirelin. One third, or more, of patients tested with protirelin may expect to experience an adverse effect. The most common side effects are nausea, an urge to micturate, and a sensation of bad taste. Other monitored adverse effects include flushed sensations, light-headedness, abdominal discomfort, headaches, dry mouth, anxiety, sweating, tightness in the throat, pressure in the chest, tingling sensations and drowsiness.

CNS: Severe headaches, with and without temporary amaurosis, have been reported in patients with pituitary tumors given TRH in combination with LHRH/GnRH. Pituitary apoplexy has developed in patients with pituitary adenomas given protirelin in combination with LHRH/GnRH and insulin. Convulsions or seizures, with and without unconsciousness, have been reported in patients with predisposing conditions of epilepsy, brain lesion, pituitary tumor, or head injury after administration of TRH or the combination TRH with LHRH/GnRH (see Warnings).

Cardiovascular: Marked changes in blood pressure, leading to clinically significant hypertension and hypotension, with or without syncope, have been reported in a small number of patients (see Warnings).

Endocrine: In postpartum patients, an increase in breast engorgement and lactation has been observed following administration of synthetic TRH.

Symptoms And Treatment Of Overdose: Symptoms: Although no specific symptoms of overdosage have been characterized in patients receiving up to 1 mg i.v. of synthetic TRH, tremors have been observed in all species of animals and at all doses tested during acute toxicity studies.

Treatment: Should any serious reaction develop, it should be treated using routine hospital procedures.

Dosage And Administration: Adults: 200 to 400 µg (0.2 to 0.4 mg). Children: 7 µg/kg (0.007 mg/kg) body weight, up to adult dose. Doses greater than 400 µg are not expected to elicit a greater TSH response.

Tests employing i.v. protirelin administration are based on the serum TSH response to a standard dose of synthetic TRH. It is essential for each laboratory to establish its own range of normal values for serum TSH before attempting quantitative assessment of TSH response to synthetic TRH administration.

When a patient is prepared for a protirelin test, the following measures should be taken: Since elevated serum lipids tend to interfere wth TSH radio-immunoassay, patients should be fasted overnight (caution is advised in patients with known hypopituitarism). Patients should be instructed to abstain from beverages containing caffeine or theophylline for 12 to 14 hours before administration of protirelins (see Drug Interactions).

Test Procedure: Blood pressure should be measured before protirelin is administered and at frequent intervals during the first 15 minutes after its administration. It is advisable to monitor blood pressure throughout the test procedure (see Warnings). The patient should be supine before, during, and for at least 15 minutes after administration of protirelin (see Warnings). Attention should be given throughout the procedure to avoid aspiration of stomach contents should nausea and possible vomiting occur. One blood sample, for baseline TSH assay, should be drawn immediately prior to the injection of protirelin. Protirelin is injected i.v. as a bolus. A second blood sample, for peak TSH assay, should be drawn at 20 to 30 minutes following protirelin injection. To detect possible delayed TSH responses, it may be necessary to draw further blood samples at 45 to 60 minutes post injection.

Availability And Storage: Each mL of solution contains: protirelin 200 µg (0.2 mg). Nonmedicinal ingredients: mannitol and sodium chloride for isotonicity and sodium phosphate monobasic as buffer. Clear glass prescored ampuls of 1 mL, boxes of 5. Store at room temperature (below 25°C), do not freeze.

RELEFACT® TRH Hoechst Marion Roussel Protirelin Synthetic Thyrotropin Releasing Hormone

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