SYNACTHEN DEPOT Suspension for injection Ref.[8607] Active ingredients: Tetracosactide

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, severe malaise or dyspnoea), Synacthen Depot or other ACTH preparations must be discontinued and 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.

Preparation should be made in advance to combat any anaphylactic reaction that may occur after an injection of Synacthen. In the event of a serious anaphylactic reaction, the patient should be treated appropriately with adrenaline and steroids.

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, kidney failure, 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 (e.g. euphoria, insomnia, mood swings, personality changes and severe depression, or even frank psychotic manifestations). Existing emotional instability or psychotic tendencies may be aggravated
• Use cautiously in patients with ocular herpes simplex owing to possible corneal perforation
• Synacthen Depot may activate latent amoebiasis. It is therefore recommended that latent or active amoebiasis be ruled out before initiating therapy.
• If Synacthen Depot is indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary because the disease may be reactivated. During prolonged therapy, such patients should receive chemoprophylaxis.
• 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.

In patients who suffer an injury or undergo surgery during or within one year after treatment, the associated stress should be managed by an increase in or resumption of treatment with Synacthen Depot. Additional use of rapidly acting corticosteroids may be required. Use the lowest effective dose to control the condition under treatment. If the dose has to be reduced, this should be done gradually. Relative insufficiency of the pituitary-adrenal axis is induced by prolonged administration, and may persist for several months after stopping treatment, so appropriate adrenocortical therapy should be considered.

Synacthen Depot contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially ‘sodium- free’.

Lack of diagnostic accuracy

Post administration total plasma cortisol levels during 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.

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

Severe jaundice has been observed for concurrent use of Synacthen and valproate in paediatric 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 oestrogens 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 (see Section 4.4 Special warnings and precautions for use).

Patients already receiving medication for diabetes mellitus or for moderate to severe hypertension must have their dosage adjusted if treatment with Synacthen Depot is started.

Women of child bearing potential

No special recommendation.

Pregnancy

There is a limited amount of data on the use of Synacthen in pregnant patients. Data from animal studies are insufficient with respect to reproductive toxicity. Synacthen should be used during pregnancy only if the expected benefit outweighs the potential risk to the foetus.

Breast-feeding

It is unknown whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Synacthen is administered to a breastfeeding woman.

Fertility

There is no data available.

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.

The following undesirable effects have been derived from post-marketing experience via spontaneous cases reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Undesirable effects are listed according to system organ classes in MedDRA. Within each system organ class, undesirable effects are presented in order of decreasing seriousness.

Table 1. Undesirable effects (frequency not known) related to tetracosactide:

Immune system disorders: Hypersenstivity*

Endocrine disorders: Adrenal haemorrhage

^* Tetracosactide can provoke hypersensitivity reactions which tend to be more severe (anaphylactic shock) in patients susceptible to allergies (especially asthma). Hypersensitivity reactions may include skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic oedema and Quincke’s oedema (see Section 4.4 Special warnings and precautions for use).

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.

Undesirable effects related to glucocorticoid and mineralocorticoid effects

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

Table 2. Undesirable effects (frequency not known) related to glucocorticoid and mineralocorticoid effects:

Infections and infestations: Abscess, infection susceptibility increased.

Blood and lymphatic system disorders: Leukocytosis.

Endocrine disorders: Cushing’s syndrome, secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, e.g. after trauma, surgery or illness; menstruation irregular, carbohydrate tolerance decreased, hyperglycaemia, manifestations of latent diabetes mellitus, hirsutism.

Metabolism and nutrition disorders: Hypokalaemia, calcium deficiency, sodium retention, fluid retention, increased appetite, hypokalaemic alkalosis.

Psychiatric disorders: Mental disorder¹

Nervous system disorders: Convulsions, benign intracranial pressure increased with papilloedema usually after treatment, vertigo, headache.

Eye disorders: Intraocular pressure increased, glaucoma, posterior subcapsular cataracts, exophthalmoses.

Cardiac disorders: Cardiac failure congestive.

Reversible cardiac hypertrophy may occur in isolated cases in infants and small children treated over a prolonged period with high doses.

Vascular disorders: Vasculitis necrotising, thromboembolism, hypertension.

Gastrointestinal disorders: Pancreatitis, peptic ulcer with possible perforation and haemorrhage, oesophagitis ulcerative, abdominal distension.

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

Musculoskeletal and connective tissue disorders: Aseptic necrosis of femoral and humeral heads, spinal compression fractures, muscle atrophy, myopathy, osteoporosis, muscular weakness, pathological fracture of long bones, tendon rupture.

General disorders and administration site conditions: Hypersensitivity reactions², growth retardation, weight increase, impaired healing.

Investigations: Nitrogen balance negative due to protein catabolism, suppression of skin test reactions.

¹ Also see Section 4.4 Special warnings and precautions for use.
² Also see Section 4.4 Special warnings and precautions for use and Section 4.8 Undesirable effects (paragraph Undesirable effects related to tetracosactide).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme by connecting to the following website: www.mhra.gov.uk/yellowcard.

None known.