SYNACTHEN AMPOULES 250 MCG
Active substance: TETRACOSACTIDE ACETATE
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SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Synacthen Ampoules 250mcg.
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Tetracosactide acetate PhEur 250micrograms per ampoule. For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
A clear colourless sterile solution in a clear glass ampoule.
4.
4.1.
CLINICAL PARTICULARS
Therapeutic indications Diagnostic test for the investigation of adrenocortical insufficiency.
4.2.
Posology and method of administration Adults: This preparation of Synacthen is intended for administration for diagnostic purposes only as a single intramuscular or intravenous dose; it is not to be used for repeated therapeutic administration. The 30-minute Synacthen diagnostic test: This test is based on measurement of the plasma cortisol concentration immediately before and exactly 30 minutes after an intramuscular or intravenous injection of 250micrograms (1ml) Synacthen. Adrenocortical function can be regarded as normal if the postinjection rise in plasma cortisol concentration amounts to at least 200nmol/litre (70micrograms/litre). Where the 30-minute test has yielded inconclusive results, or where it is desired to determine the functional reserve of the adrenal cortex, a 5-hour test can be performed with Synacthen Depot (see separate Summary of Product Characteristics). Furthermore, a 3-day test with Synacthen Depot may be used to differentiate between primary and secondary adrenocortical insufficiency.
Children: An intravenous dose of 250micrograms/1.73m2 body surface area has been suggested. Thus for children aged 5 to 7 years, approximately half the adult dose will be adequate. For more accurate dosing of other ages, standard body surface area tables should be consulted. Elderly: There is no evidence to suggest that dosage should be different in the elderly.
4.3
Contraindications
History of hypersensitivity to Adrenocorticotropic hormone (ACTH), Synacthen or Synacthen Depot. Synacthen is contra-indicated in patients with allergic disorders (e.g. asthma) (see Section 4.4 Special warnings and special precautions for use), acute psychosis, infectious diseases, peptic ulcer, refractory heart failure, Cushings syndrome, and primary adrenocortical insufficiency. Synacthen Ampoules should not be used during pregnancy or lactation unless there are compelling reasons to do so. 4.4 Special warnings and precautions for use 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 or dyspnoea), Synacthen or other ACTH preparations 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 occurring, 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 100mg 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 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. The increased production of adrenal steroids may result in corticosteroid type effects: 4.5 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). Dosage adjustments may be necessary in patients being treated for diabetes or hypertension.
Interaction with other medicinal products and other forms of interaction 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 special 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. Synacthen contains an active substance that may interfere with routine drug testing in athletes.
4.6
Fertility, pregnancy and lactation
Usage in 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). Usage in pregnancy is contraindicated (see Section 4.3 Contraindications). Therefore the Synacthen test should not be utilised during pregnancy unless there are compelling reasons for doing so. Usage in lactation: It is not known whether tetracosactide enters breast milk or not. Usage in lactation is contraindicated (see Section 4.3 Contraindications). Fertility: Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 Preclinical safety data).
4.7.
Effects on ability to drive and use machines Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness.
4.8
Undesirable effects
Synacthen 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 Contra-indications). Hypersensitivity may be manifested as skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic oedema and Quinke'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 Summary of Product Characteristics. Adverse reactions in Table 1 are ranked under heading of frequency where known, the most frequent first, using the following convention: very common (greater than or equal to 1 in 10); common (less than or equal to 1 in 100, less than 1 in 10); uncommon (greater than or equal to 1 in 1,000, less than 1 in 100); rare (greater than or less than 1 in 10,000, less than 1 in 1,000) very rare (less than 1 in 10,000), not known (where no valid estimate of the incidence has been derived).
Table 1. Adverse events
Infections and infestations Not known Not known Immune system disorders Not Known Anaphylactic shock, skin reactions at the injection site, urticaria, angioneurotic oedema, Quinke's oedema Menstruation irregular, Cushingss syndrome, secondary adrenocortical and pituitary unresponsiveness. Decreased carbohydrate tolerance, hyperglycaemia, manifestations of latent diabetes mellitus, hirsutism1) Adrenal haemorrhage Increased appetite, hypokalaemia, calcium deficiency, sodium retention, fluid retention Increased susceptibility to infection, abscess Leukocytosis Blood and the lymphatic system disorders
Endocrine disorders Not known
Metabolism and nutrition disorders Not known
Psychiatric disorders Not known Nervous system disorders Not known Headache, vertigo, convulsions, dizziness Benign intracranial pressure with papilloedema, usually after treatment Posterior sub capsular cataracts, increased intraocular pressure, glaucoma, exophthalmoses Cardiac failure congestive, blood pressure increase. Dyspnoea Thromboembolism, necrotising vasculitis Peptic ulcer with possible perforation and haemorrhage, pancreatitis, abdominal distension, oesophagitis ulcerative Nausea, vomiting Skin atrophy, petechiae and ecchymosis, erythema, hyperhidrosis, acne and skin hyper pigmentation, pruritus, urticaria Osteoporosis, muscular weakness, myopathy steroid, loss of muscle mass, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fracture of long bones, tendon rupture Hypersensitivity reactions2) , weight increased, impaired healing, growth retardation, flushing, malaise Negative nitrogen balance due to protein catabolism, suppression of skin test reactions Mental disorder2)
Eye disorders Not known Cardiac disorders Not known Vascular disorders Not known Gastrointestinal disorders Not known
Skin and subcutaneous tissue disorders Not known
Musculoskeletal, connective tissue and bone disorders Not known
General disorders and administration site conditions Not known
Investigations Not known
1) Particularly in times of stress, e.g. after trauma, surgery, or illness 2) Refer to section 4.4
4.9.
Overdose
Overdosage is unlikely to be a problem when the product is used as a single dose for diagnostic purposes.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: anterior pituitary lobe hormones and analogues ACTH. ATC code: H01AA02. 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. 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.
5.2.
Pharmacokinetic properties Following an intravenous injection, elimination of tetracosactide acetate from the plasma consists of 3 phases. The half-lives of these phases are approximately 7 minutes (0 to 1 hour), 37 minutes (1 to 2 hours) and 3 hours thereafter. Tetracosactide acetate has an apparent volume of distribution of approximately 0.4 L/kg. In the serum, tetracosactide acetate is broken down by serum endopeptidases into inactive oligopeptides and then by aminopeptidases into free amino acids. The rapid elimination from plasma is probably not attributable to this relatively slow cleavage process, but rather to the rapid concentration of the active substance in the adrenal glands and kidneys. Following an iv dose of 1311-labelled tetracosactide acetate, 95 to 100% of the radioactivity is excreted in the urine within 24 hours.
5.3.
Preclinical safety data
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.
6.
6.1.
PHARMACEUTICAL PARTICULARS
List of excipients Acetic acid, sodium acetate, sodium chloride and water.
6.2.
Incompatibilities None known.
6.3.
Shelf life 5 years.
6.4.
Special precautions for storage Synacthen should be protected from light and stored in a refrigerator (2 - 8C).
6.5.
Nature and contents of container The ampoules are colourless glass PhEur type I. Five ampoules are packed in a cardboard box.
6.6
Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. MARKETING AUTHORISATION HOLDER
7.
Alliance Pharmaceuticals Ltd Avonbridge House Bath Road Chippenham Wiltshire SN15 2BB
8.
MARKETING AUTHORISATION NUMBER(S) PL 16853/0017
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25 June 1998
10
DATE OF REVISION OF THE TEXT
04/01/2011
1
NAME OF THE MEDICINAL PRODUCT
Synacthen Ampoules 250mcg.
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Tetracosactide acetate PhEur 250micrograms per ampoule. For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
A clear colourless sterile solution in a clear glass ampoule.
4.
4.1.
CLINICAL PARTICULARS
Therapeutic indications Diagnostic test for the investigation of adrenocortical insufficiency.
4.2.
Posology and method of administration Adults: This preparation of Synacthen is intended for administration for diagnostic purposes only as a single intramuscular or intravenous dose; it is not to be used for repeated therapeutic administration. The 30-minute Synacthen diagnostic test: This test is based on measurement of the plasma cortisol concentration immediately before and exactly 30 minutes after an intramuscular or intravenous injection of 250micrograms (1ml) Synacthen. Adrenocortical function can be regarded as normal if the postinjection rise in plasma cortisol concentration amounts to at least 200nmol/litre (70micrograms/litre). Where the 30-minute test has yielded inconclusive results, or where it is desired to determine the functional reserve of the adrenal cortex, a 5-hour test can be performed with Synacthen Depot (see separate Summary of Product Characteristics). Furthermore, a 3-day test with Synacthen Depot may be used to differentiate between primary and secondary adrenocortical insufficiency.
Children: An intravenous dose of 250micrograms/1.73m2 body surface area has been suggested. Thus for children aged 5 to 7 years, approximately half the adult dose will be adequate. For more accurate dosing of other ages, standard body surface area tables should be consulted. Elderly: There is no evidence to suggest that dosage should be different in the elderly.
4.3
Contraindications
History of hypersensitivity to Adrenocorticotropic hormone (ACTH), Synacthen or Synacthen Depot. Synacthen is contra-indicated in patients with allergic disorders (e.g. asthma) (see Section 4.4 Special warnings and special precautions for use), acute psychosis, infectious diseases, peptic ulcer, refractory heart failure, Cushings syndrome, and primary adrenocortical insufficiency. Synacthen Ampoules should not be used during pregnancy or lactation unless there are compelling reasons to do so. 4.4 Special warnings and precautions for use 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 or dyspnoea), Synacthen or other ACTH preparations 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 occurring, 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 100mg 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 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. The increased production of adrenal steroids may result in corticosteroid type effects: 4.5 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). Dosage adjustments may be necessary in patients being treated for diabetes or hypertension.
Interaction with other medicinal products and other forms of interaction 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 special 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. Synacthen contains an active substance that may interfere with routine drug testing in athletes.
4.6
Fertility, pregnancy and lactation
Usage in 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). Usage in pregnancy is contraindicated (see Section 4.3 Contraindications). Therefore the Synacthen test should not be utilised during pregnancy unless there are compelling reasons for doing so. Usage in lactation: It is not known whether tetracosactide enters breast milk or not. Usage in lactation is contraindicated (see Section 4.3 Contraindications). Fertility: Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 Preclinical safety data).
4.7.
Effects on ability to drive and use machines Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness.
4.8
Undesirable effects
Synacthen 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 Contra-indications). Hypersensitivity may be manifested as skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic oedema and Quinke'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 Summary of Product Characteristics. Adverse reactions in Table 1 are ranked under heading of frequency where known, the most frequent first, using the following convention: very common (greater than or equal to 1 in 10); common (less than or equal to 1 in 100, less than 1 in 10); uncommon (greater than or equal to 1 in 1,000, less than 1 in 100); rare (greater than or less than 1 in 10,000, less than 1 in 1,000) very rare (less than 1 in 10,000), not known (where no valid estimate of the incidence has been derived).
Table 1. Adverse events
Infections and infestations Not known Not known Immune system disorders Not Known Anaphylactic shock, skin reactions at the injection site, urticaria, angioneurotic oedema, Quinke's oedema Menstruation irregular, Cushingss syndrome, secondary adrenocortical and pituitary unresponsiveness. Decreased carbohydrate tolerance, hyperglycaemia, manifestations of latent diabetes mellitus, hirsutism1) Adrenal haemorrhage Increased appetite, hypokalaemia, calcium deficiency, sodium retention, fluid retention Increased susceptibility to infection, abscess Leukocytosis Blood and the lymphatic system disorders
Endocrine disorders Not known
Metabolism and nutrition disorders Not known
Psychiatric disorders Not known Nervous system disorders Not known Headache, vertigo, convulsions, dizziness Benign intracranial pressure with papilloedema, usually after treatment Posterior sub capsular cataracts, increased intraocular pressure, glaucoma, exophthalmoses Cardiac failure congestive, blood pressure increase. Dyspnoea Thromboembolism, necrotising vasculitis Peptic ulcer with possible perforation and haemorrhage, pancreatitis, abdominal distension, oesophagitis ulcerative Nausea, vomiting Skin atrophy, petechiae and ecchymosis, erythema, hyperhidrosis, acne and skin hyper pigmentation, pruritus, urticaria Osteoporosis, muscular weakness, myopathy steroid, loss of muscle mass, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fracture of long bones, tendon rupture Hypersensitivity reactions2) , weight increased, impaired healing, growth retardation, flushing, malaise Negative nitrogen balance due to protein catabolism, suppression of skin test reactions Mental disorder2)
Eye disorders Not known Cardiac disorders Not known Vascular disorders Not known Gastrointestinal disorders Not known
Skin and subcutaneous tissue disorders Not known
Musculoskeletal, connective tissue and bone disorders Not known
General disorders and administration site conditions Not known
Investigations Not known
1) Particularly in times of stress, e.g. after trauma, surgery, or illness 2) Refer to section 4.4
4.9.
Overdose
Overdosage is unlikely to be a problem when the product is used as a single dose for diagnostic purposes.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: anterior pituitary lobe hormones and analogues ACTH. ATC code: H01AA02. 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. 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.
5.2.
Pharmacokinetic properties Following an intravenous injection, elimination of tetracosactide acetate from the plasma consists of 3 phases. The half-lives of these phases are approximately 7 minutes (0 to 1 hour), 37 minutes (1 to 2 hours) and 3 hours thereafter. Tetracosactide acetate has an apparent volume of distribution of approximately 0.4 L/kg. In the serum, tetracosactide acetate is broken down by serum endopeptidases into inactive oligopeptides and then by aminopeptidases into free amino acids. The rapid elimination from plasma is probably not attributable to this relatively slow cleavage process, but rather to the rapid concentration of the active substance in the adrenal glands and kidneys. Following an iv dose of 1311-labelled tetracosactide acetate, 95 to 100% of the radioactivity is excreted in the urine within 24 hours.
5.3.
Preclinical safety data
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.
6.
6.1.
PHARMACEUTICAL PARTICULARS
List of excipients Acetic acid, sodium acetate, sodium chloride and water.
6.2.
Incompatibilities None known.
6.3.
Shelf life 5 years.
6.4.
Special precautions for storage Synacthen should be protected from light and stored in a refrigerator (2 - 8C).
6.5.
Nature and contents of container The ampoules are colourless glass PhEur type I. Five ampoules are packed in a cardboard box.
6.6
Special precautions for disposal and other handling Any unused product or waste material should be disposed of in accordance with local requirements. MARKETING AUTHORISATION HOLDER
7.
Alliance Pharmaceuticals Ltd Avonbridge House Bath Road Chippenham Wiltshire SN15 2BB
8.
MARKETING AUTHORISATION NUMBER(S) PL 16853/0017
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 25 June 1998
10
DATE OF REVISION OF THE TEXT
04/01/2011
Source: Medicines and Healthcare Products Regulatory Agency
Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
