Synacthen Depot^® Ampoules 1mg/ml

Tetracosactide acetate PhEur 1mg/ml

Contains benzyl alcohol (50mg/5ml), for a full list of excipients, see sections 6.1

Tetracosactide acetate is absorbed on to zinc phosphate. A sterile, milky white suspension, which settles on standing, in a clear glass ampoule.

Therapeutic use: Synacthen Depot should normally only be used for short-term therapy in conditions for which glucocorticoids are indicated in principle, for example, in ulcerative colitis and Crohn's disease, juvenile rheumatoid arthritis, or as adjunct therapy in patients with rheumatoid arthritis and osteoarthrosis. Synacthen Depot may be particularly useful in patients unable to tolerate oral glucocorticoid therapy or in patients where normal therapeutic doses of glucocorticoids have been ineffective.

Diagnostic use: As a diagnostic aid for the investigation of adrenocortical insufficiency.

Synacthen Depot is intended for intramuscular injection. The ampoule should be shaken before use.

Therapeutic use: Initially, daily doses of Synacthen Depot should be given but after approximately 3 days, intermittent doses may be given.

Adults: Initially 1mg intramuscularly daily or 1mg every 12 hours in acute cases. After the acute symptoms of the disease have disappeared, treatment may be continued at a dose of 1mg every 2 to 3 days; in patients who respond well, the dosage may be reduced to 0.5mg every 2 to 3 days or 1mg per week.

Infants and children under 3 years: Not recommended due to the presence of benzyl alcohol in the formulation.

Children aged 3 to 5 years: Initially 0.25 to 0.5mg intramuscularly daily; the maintenance dose is 0.25 to 0.5mg every 2 to 8 days.

Children aged 5 to 12 years: Initially 0.25 to 1mg intramuscularly daily; the maintenance dose is 0.25 to 1mg every 2 to 8 days.

Elderly: There is no evidence to suggest that dosage should be different in the elderly.

Diagnostic use: In cases of suspected adrenocortical insufficiency, where the 30-minute diagnostic test with Synacthen ampoules (see Synacthen Summary of Product Characteristics) has yielded inconclusive results or where it is desired to determine the functional reserve of the adrenal cortex, a 5-hour test with Synacthen Depot may be performed.

Adults: This test is based on measurement of the plasma cortisol concentration before and exactly 30 minutes, 1, 2, 3, 4 and 5 hours after an intramuscular injection of 1mg Synacthen Depot. Adrenocortical function can be regarded as normal if the post-injection rise in plasma cortisol concentration increases 2-fold in the first hour, and continues to rise steadily. The values expected would be 600 to 1,250nmol/l in the first hour increasing slowly up to 1,000 to 1,800nmol/l by the fifth hour. Lower concentrations of plasma cortisol may be attributable to Addison's disease, secondary adrenocortical insufficiency due to a disorder of hypothalamo-pituitary function, or overdosage of corticosteroids.

A 3-day test with Synacthen Depot may be used to differentiate between primary and secondary adrenocortical insufficiency.

Children: No paediatric dosage has been established. Synacthen Depot is not recommended for children under 3 years of age due to the presence of benzyl alcohol in the formulation.

Elderly: There is no evidence to suggest that dosage should be different in the elderly.

History of hypersensitivity to ACTH, Synacthen or Synacthen Depot. Acute psychoses, infectious diseases, Cushing's syndrome, peptic ulcer, refractory heart failure, adrenogenital syndrome and for therapeutic use in adrenocortical insufficiency.

In view of the increased risk of anaphylactic reactions, Synacthen Depot should not be used in patients known to have asthma and/or other forms of allergy.

Synacthen Depot is contra-indicated for use in children under 3 years of age as it contains benzyl alcohol, which can cause severe poisoning and hypersensitivity reactions.

Therapeutic use is contra-indicated during pregnancy or lactation. Diagnostic use should only occur during pregnancy or lactation if there are compelling reasons.

Synacthen Depot must not be administered intravenously.

Before using Synacthen Depot, the doctor should make every effort to find out whether the patient is suffering from, or has a history of, allergic disorders. In particular, he should enquire whether the patient has previously experienced adverse reactions to ACTH, Synacthen Depot or other drugs.

Synacthen Depot should only be administered under medical supervision.

If local or systemic hypersensitivity reactions occur during or after an injection (for example, marked redness and pain at the injection site, urticaria, pruritus, flushing, faintness or dyspnoea), Synacthen Depot or other ACTH preparations should be avoided in the future. Hypersensitivity reactions tend to occur within 30 minutes of the injection. The patient should therefore be kept under observation during this time.

In the event of a serious anaphylactic reaction occurring despite these precautions, the following measures must be taken immediately: administer adrenaline (0.4 to 1ml of a 0.1% solution intramuscularly or 0.1 to 0.2ml of a 0.1% solution in 10ml physiological saline slowly intravenously) as well as a large intravenous dose of a corticosteroid (for example 100 to 500mg hydrocortisone, three or four times in 24 hours) repeating the dose if necessary.

The hydrocortisone product information prepared by the manufacturer should also be consulted.

Synacthen Depot should not be used in the presence of active infectious or systemic diseases, when the use of live vaccine is contemplated or in the presence of a reduced immune response, unless adequate disease specific therapy is being given.

Use with care in patients with non-specific ulcerative colitis, diverticulitis, recent intestinal anastomosis, renal insufficiency, hypertension, thromboembolic tendencies, osteoporosis and myasthenia gravis.

The increased production of adrenal steroids may result in corticosteroid type effects:

- Salt and water retention can occur and may respond to a low salt diet. Potassium supplementation may be necessary during long term treatment.

- Psychological disturbances may be triggered or aggravated.

- Latent infections (e.g. amoebiasis, tuberculosis) may become activated.

- Ocular effects may be produced (e.g. glaucoma, cataracts).

- Provided the dose is chosen to meet the individual's needs, Synacthen Depot is unlikely to inhibit growth in children. Nevertheless, growth should be monitored in children undergoing long-term treatment. In infants and children aged up to 5 years, reversible myocardial hypertrophy may occur in very rare cases following long-term treatment with high doses. Therefore echocardiographic recordings should be made regularly.

- Dosage adjustments may be necessary in patients being treated for diabetes or hypertension.

An enhanced effect of tetracosactide acetate therapy may occur in patients with hypothyroidism and in those with cirrhosis of the liver.

Interactions are likely with drugs whose actions are affected by adrenal steroids (see Section 4.4 “Special warnings and precautions for use”).

Synacthen Depot is contra-indicated for therapeutic use during pregnancy and lactation. It should not be used as a diagnostic tool unless there are compelling reasons for doing so.

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness.

Since Synacthen Depot stimulates the adrenal cortex to increase the output of glucocorticoids and mineralocorticoids, side effects associated with excessive adrenocorticotropic activity may be encountered, as well as those related to tetracosactide and to the presence of benzyl alcohol in the formulation.

Undesirable effects related to tetracosactide

Immune system disorders: Synacthen Depot may provoke hypersensitivity reactions. In patients suffering from, or susceptible to, allergic disorders (especially asthma) this may take the form of anaphylactic shock (see Section 4.3 Contraindications).

Hypersensitivity may be manifested as skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic oedema and Quincke's oedema.

Endocrine disorders: Adrenal haemorrhage (very rare)

Undesirable effects related to benzyl alcohol

The benzyl alcohol contained as an excipient in Synacthen Depot may provoke toxic and anaphylactoid reactions in children aged under 3 years (see Section 4.3 Contraindications, Section 4.4 Special warnings and special precautions for use).

Immune system disorders: Hypersensitivity reactions

Undesirable effects related to glucocorticoid and mineralocorticoid effects

The undesirable effects related to glucocorticoid and mineralocorticoid effects are unlikely to be observed with short-tem use of Synacthen Depot as a diagnostic tool, but may be reported when Synacthen Depot is used for therapeutic indications.

Infections and infestations: Increased susceptibility to infection, abscess.

Blood and lymphatic system disorders: Leucocytosis.

Endocrine disorders: Menstrual irregularities, Cushing's syndrome, secondary adrenocortical and pituitary insufficiency, particularly in times of stress, as in trauma, surgery or illness, decreased carbohydrate tolerance, hyperglycaemia, manifestations of latent diabetes mellitus, hirsutism.

Metabolism and nutrition disorders: Sodium retention, fluid retention, hypokalaemia, hypokalaemic alkalosis, calcium loss, increased appetite.

Psychiatric disorders: Mental disorder.

Nervous system disorders: Headache, convulsions, increased intracranial pressure with papilloedema (benign intracranial hypertension) usually after treatment.

Eye disorders: Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos.

Ear and labyrinth disorders: Vertigo.

Cardiac disorders: Blood pressure increased, congestive heart failure. There have been very rare reports of reversible myocardial hypertrophy in infants and small children treated over a prolonged period with high doses.

Vascular disorders: Thromboembolism, necrotising vasculitis.

Gastrointestinal disorders: Peptic ulceration with possible perforation and haemorrhage, pancreatitis, abdominal distension, ulcerative oesophagitis.

Skin and subcutaneous tissue disorders: Skin atrophy, petechia, ecchymosis, facial erythema, hyperhidrosis, acne, skin hyperpigmentation.

Musculoskeletal, connective tissue and bone disorders: Osteoporosis, muscle weakness, steroid myopathy, loss of muscle mass, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathologic fracture of long bones, tendon rupture.

General disorders and administration site conditions: Impaired wound healing, growth retardation in children.

Investigations: Weight increase, suppression of skin test reactions, negative nitrogen balance due to protein catabolism.

Relating to therapeutic usage of Synacthen Depot:

Overdosage may lead to fluid retention and signs of excessive adrenocorticotropic activity (Cushing's Syndrome). In such cases, Synacthen Depot should either be withdrawn temporarily, given in lower doses or the interval between injections should be prolonged (e.g. 5 to 7 days).

Treatment: There is no known antidote. Treatment should be symptomatic.

Tetracosactide acetate consists of the first 24 amino acids occurring in the natural corticotropic hormone (ACTH) sequence and displays the same physiological properties as ACTH. In the adrenal cortex, it stimulates the biosynthesis of glucocorticoids, mineralocorticoids, and, to a lesser extent, androgens, which explains its therapeutic effect in conditions responsive to glucocorticoid treatment.

However, its pharmacological activity is not comparable to that of corticosteroids, because under ACTH treatment (in contrast to treatment with a single glucocorticoid) the tissues are exposed to a physiological spectrum of corticosteroids.

The site of action of ACTH is the plasma membrane of the adrenocortical cells, where it binds to a specific receptor. The hormone-receptor complex activates adenylate cyclase, stimulating the production of cyclic AMP (adenosine monophosphate) and so promoting the synthesis of pregnenolone from cholesterol. From pregnenolone the various corticosteroids are produced via different enzymatic pathways.

Tetracosactide acetate is absorbed on to a zinc phosphate complex which ensures the sustained release of the active substance from the intramuscular injection site. After an intramuscular injection of 1mg Synacthen Depot, the radioimmunologically determined plasma concentrations of tetracosactide acetate range between 200 to 300pg/ml and are maintained for 12 hours.

Tetracosactide acetate has an apparent volume of distribution of approximately 0.4litres/kg.

In the serum, tetracosactide acetate is broken down by serum endopeptidases into inactive oligopeptides and then by aminopeptidases into free amino acids.

Following an intravenous dose of ¹³¹I-labelled tetracosactide acetate, 95 to 100% of the radioactivity is excreted in the urine within 24 hours.

There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.

Zinc chloride, disodium phosphate dodecahydrate, benzyl alcohol, sodium chloride, sodium hydroxide and water for injections.

None known

3 years

Protect from light. Store in a refrigerator (2 to 8C).

1ml ampoules packed in boxes of 10.

None

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

PL16853/0018

25 June 1998

February 2007