Active ingredient: tetracosactrin Empirical formula: C136H210N40O31S Molecular weight: 2933.5 Amino acid sequence: Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys- Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro

DESCRIPTION

Synacthen is the first corticotrophic preparation to be produced entirely by synthesis and displays all of the pharmacological properties of endogenous ACTH. It is a long-chain polypeptide composed of the first 24 of the 39 amino acids contained in the naturally occurring ACTH (corticotrophin) molecule. In contrast to ACTH preparations obtained by extraction, the composition of Synacthen is not subject to variation, so that dosage can be expressed in terms of weight. For the purposes of clinical use, Synacthen 1mg corresponds approximately to 100 international units of ACTH (as defined in the Third International Working Standard). Studies have shown that a single test dose of Synacthen 250 micrograms (corresponding to 25 IU) administered by intramuscular injection is sufficient to elicit a marked rise in plasma cortisol within 30 minutes. Synacthen ampoules contain 250 micrograms tetracosactrin (as the hexa-acetate salt) per 1 mL of solution. Excipients: acetic acid, sodium acetate, sodium chloride, water for injections.

PHARMACOLOGY

Synacthen has the same physiological action as endogenous ACTH. In the normally functioning adrenal cortex it stimulates the biosynthesis of glucocorticoids, mineralocorticoids and (to a lesser extent) androgens. This accounts for its therapeutic effect in conditions responsive to glucocorticoid treatment. Its pharmacological activity, however, is not comparable to that of the corticosteroids because under ACTH treatment, in contrast to treatment with a single glucocorticoid, the tissues are exposed to a physiological spectrum of corticosteroids such as desoxycorticosterone, corticosterone, cortisol and aldosterone. Prolonged treatment with high doses of ACTH induces hyperplasia and hypertrophy of the adrenal cortex and continuous high output of cortisol, corticosterone and weak androgens. The binding sites of ACTH are located in the plasma membrane of the adrenocortical cells, where it becomes bound to a specific receptor. The hormone-receptor complex activates adenyl cyclase, thereby stimulating the production of cyclic AMP (adenosine monophosphate). Cyclic AMP activates protein kinase, which promotes the synthesis of pregnenolone from cholesterol. From pregnenolone the various corticosteroids are produced via a variety of enzymatic pathways.

Tetracosactrin has an apparent distribution volume of approx. 0.4 litres/kg. The half-lives of its elimination from the plasma following an intravenous injection are approximately 7 minutes in the first phase (lasting approximately 1 hour), approximately 37 minutes in the next phase (also lasting approximately 1 hour) and, thereafter, approximately 3 hours. In the serum, tetracosactrin is broken down first by serum endopeptidases (such as trypsin, plasmin, thrombin, and kallikrein) into inactive oligopeptides, and then by aminopeptidases into free amino acids. Its rapid elimination from the plasma is probably attributable, not only to this relatively slow process of cleavage, but rather to the fact that the active substance becomes rapidly concentrated in the adrenals and kidneys. Following an intravenous dose of 131I - labelled beta 1-24-corticotrophin, 95 to 100% of the radioactivity is excreted in the urine within 24 hours.

CONTRAINDICATIONS

In view of the increased risk of anaphylactic reactions, Synacthen as a diagnostic agent is not recommended in patients with asthma or other allergic conditions (see "PRECAUTIONS- Hypersensitivity").

PRECAUTIONS

Before employing Synacthen the physician must ascertain whether the patient is suffering from an allergic disorder (especially asthma) or is susceptible in general to allergies. He should also enquire whether the patient has been treated with ACTH preparations in the past, and if so, ensure that the treatment did not give rise to hypersensitivity reactions (see "CONTRAINDICATIONS"). In rare instances in patients without a history of allergy, but more frequently in the presence of a history of asthma or other forms of allergy, severe anaphylactic reactions have occurred, some with fatal outcome. Usually, such reactions were manifest within 30 minutes of administration of Synacthen. In these allergic patients, the Synacthen test should only be performed if no ACTH preparations have previously been given. The physician must at all events be prepared in advance to combat at once any anaphylactic reaction occurring after the injection of Synacthen. Hypersensitivity reactions tend to occur within 30 minutes of injection. The patient should be kept under observation during this time. Should a serious anaphylactic reaction occur, despite all precautions, the following immediate measures must be taken: administer adrenaline (0.4 to 1 mL of a 1 mg/mL solution intramuscularly or 0.1 to 0.2 mL of a 1 mg/mL solution in 10 mL physiological saline slowly intravenously), as well as large intravenous doses of water- soluble corticosteroids, repeating the dose if necessary. If local or systemic hypersensitivity reactions occur during or after an injection (e.g. marked redness and pain at the injection site, urticaria, pruritus, flushing, severe malaise or dyspnoea), all use of ACTH preparations must be avoided in the future.

Synacthen should be used with caution in patients with diabetes mellitus or moderate to severe hypertension.

Since Synacthen may have an effect on the central nervous system, patients should be cautious when driving a vehicle or operating machinery.

Appropriate studies have not been performed to evaluate carcinogenic or mutagenic potential, or impairment of fertility.

There have been some reports of miscarriage or fetal malformation occurring in pregnant women treated with tetracosactrin. Therefore, Synacthen must not be administered during pregnancy.

The administration of tetracosactrin during lactation has not been reported. Any decision to administer Synacthen as a diagnostic aid must be with recognition to the individual case history. Mothers must not breastfeed during the period of its use.

Patients receiving cortisone or hydrocortisone on the test day may exhibit abnormally high baseline plasma cortisol concentrations and a paradoxical decrease in plasma cortisol concentrations following administration of Synacthen. Patients should not receive pretest doses of cortisone or hydrocortisone on the day of testing.

Severe jaundice has been observed for concurrent use of Synacthen and valproate in pediatric population. Their concurrent use should be avoided.

Concurrent use of Synacthen and other anticonvulsants (e.g. phenytoin, clonazepam, nitrazepam, phenobarbital, primidone) may increase the risk of liver damage, thus, Synacthen should be used with caution at minimum possible doses and for minimum duration for concurrent treatment. Endogenous and synthetic estrogens can cause an increase in total cortisol levels and therefore, it is considered appropriate to use alternative methods (e.g., salivary cortisol, free cortisol index, plasma free cortisol) for interpretation of the results of the HPA axis examination. Live virus immunisation procedures must not be undertaken during treatment with Synacthen because of the decrease in antibody response.

Post administration total plasma cortisol levels during the Synacthen test might be misleading in some special clinical situations due to altered cortisol binding globulin levels. These situations include patients on oral contraceptives, post operative patients, critical illness, severe liver disease, nephrotic syndrome. Hence in these circumstances, alternative parameters (e.g., salivary cortisol, free cortisol index, plasma free cortisol) can be used to assess the integrity of HPA axis. Because spironolactone metabolites fluoresce, erroneously high plasma cortisol concentrations may be reported in patients receiving spironolactone when fluorometric analysis is used but not when radioimmunoassay or competitive protein binding methods are used. Therefore, patients should not receive pretest doses of spironolactone on the day of testing when the fluorometric method is used. Since prednisone, dexamethasone and betamethasone are not detectable by the fluorometric method, therapy with these drugs can be maintained. In patients with increased plasma bilirubin concentrations or with free haemoglobin in their plasma, falsely elevated fluorescence measurements may occur. Synacthen contains an active substance that may interfere with routine drug testing in athletes.

ADVERSE REACTIONS

Frequency estimate: very common 10%; common 1% to <10%; uncommon 0.1% to <1%; rare 0.01% to <0.1%; very rare <0.01%.

Hypersensitivity reactions:

Rare:

Synacthen may provoke hypersensitivity reactions which tend to be more severe (anaphylactic shock) in patients susceptible to allergies, especially asthma (see "PRECAUTIONS-Hypersensitivity"). Hypersensitivity reactions may include skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, flushing, malaise, dyspnoea, angioneurotic oedema or Quincke's oedema.

Adrenal haemorrhage

: isolated cases have been reported with Synacthen.

DOSAGE AND ADMINISTRATION

Refer to "PRECAUTIONS-Interaction with Other Drugs and Effects on Laboratory Tests" for information on drugs that may interfere with test results.

This test is based on the increase in plasma cortisol recorded 30 minutes after an intramuscular injection of Synacthen 250 micrograms. Two blood specimens should be taken, the first immediately before and the second exactly 30 minutes after the injection of Synacthen. If the plasma cortisol rises to at least 200 nanomoles/L (70 micrograms/L) above the initial level, or if the plasma cortisol level attained 30 minutes after injection exceeds 500 nanomoles/L (180 micrograms/L), irrespective of the basal level, then adrenocortical function can be regarded as normal.

OVERDOSAGE

There have not been any reports that administration of Synacthen, in recommended dosage as a diagnostic aid, has resulted in signs and symptoms associated with overdosage. However, for information on this subject, reference may be made to the Product Information for Synacthen Depot.

PRESENTATION

Injection: 250 micrograms/mL, 1 mL ampoule; containers of 1. Storage: protect from light and store in a refrigerator (2-8oC).

SPONSOR

NOVARTIS Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road NORTH RYDE NSW 2113

Approved by Therapeutic Goods Administration: 12 August 1999 Date of most recent amendment: 10 January 2012

NAME OF THE DRUG