SYNACTHEN Solution for injection or infusion Ref.[27686] Active ingredients: Tetracosactide

Before using Synacthen, the doctor should make every effort to find out whether the patient is suffering from, or has a history of, allergic disorders (see Section 4.3 “Contra-indications”). In particular, he should enquire whether the patient has previously experienced adverse reactions to ACTH, Synacthen or other drugs.

Synacthen should only be administered under the supervision of appropriate senior hospital medical staff (e.g. consultants).

If local or systemic hypersensitivity reactions occur after the injection (for example, marked redness and pain at the injection site, urticaria, pruritus, flushing, faintness, severe malaise or dyspnoea), Synacthen or other ACTH preparations must be discontinued and should be avoided in the future. Hypersensitivity reactions tend to occur within 30 minutes of an 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 Ampoules 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 hypertension and thromboembolic tendencies.

Use cautiously in patients with ocular herpes simplex owing to possible corneal perforation.

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

• 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
• Latent infections (e.g. amoebiasis, tuberculosis) may become activated
• Ocular effects may be produced (e.g. glaucoma, cataracts)
• Dosage adjustments may be necessary in patients being treated for diabetes or hypertension
• If Synacthen is used in any of the following conditions, the risks of treatment should be weighed against the possible benefits: ulcerative colitis, diverticulitis, recent intestinal anastomosis, kidney failure, hypertension, predisposition to thromboembolism, osteoporosis, myasthenia gravis.

The solution for injection 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.

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).

Since Synacthen increases the adrenocortical production of glucocorticoids and mineralocorticoids, drug interactions of the type seen with these corticosteroids may occur (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 is started.

Pregnancy

There is limited amount of data in the use of tetracosactide in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 Preclinical safety data). Synacthen should be used during pregnancy only if the expected benefit outweighs the potential risk to the foetus.

Breast-feeding

It is not known whether tetracosactide enters breast milk or not. Because many drugs are excreted in human milk, caution should be exercised when Synacthen is administered to a breastfeeding woman.

Fertility

Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 Preclinical safety data).

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

Undesirable effects may be related to tetracosactide or to the stimulation of glucocorticoids and mineralocorticoid secretion during the use of Synacthen.

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.

The undesirable effects related to glucocorticoid and mineralocorticoid effects are unlikely to be observed with short-term use of Synacthen as a diagnostic tool, but may be reported when Synacthen is used in therapeutic indications. Should information be required on the side effects reported with therapeutic use of tetracosactide acetate, see Synacthen Depot Ampoules 1 mg/ml Summary of Product Characteristics.

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

Infections and infestations: Abscess. Infection susceptibility increased

Blood and the 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

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 sub capsular 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 and ecchymosis, erythema, hyperhidrosis, acne and skin hyper pigmentation

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

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

Investigations: Negative nitrogen balance due to protein catabolism, suppression of skin test reactions

¹ Also see section 4.4 Special warnings and precautions for use
² Also see 4.4. Special warnings and precautions for use and Table 1 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.