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SYNACTHEN® DEPOT Novartis Pharmaceuticals Cosyntropin--Zinc Hydroxide Adrenocorticotropic Hormone
 
Action and Clinical

Natural adrenocorticotropin is a straight-chain polypeptide containing 39 amino acids which, by convention, are numbered from the N terminal end of the molecule. The sequence of amino-acid occupying positions 25 to 33 varies among species and it is this part of the molecule which is most antigenic when ACTH of foreign origin is administered to man. In contrast, the N terminal 24 amino-acid sequence is common to all species and is relatively non-antigenic, and it is only these amino-acids which are involved in its biological activities.:

The most important physiological effects of ACTH involve the adrenal cortex and include the maintenance of adrenal weight and the control of adrenal corticosteroid synthesis and release. In its absence, adrenal blood flow is diminished, adrenal atrophy invariably ensues and cortisol secretion is markedly reduced. In addition to controlling corticosteroid secretion, ACTH also increases the synthesis and release of the other adrenal steroids, namely aldosterone and the adrenal androgens. It also has some degree of melanotropic activity and lipolytic effect.

Synacthen Depot, a long-acting synthetic b1-24-corticotropin, exhibits the same activity as natural ACTH with regard to all its biological activities. The complex results in a product whose absorption in man is effected over a longer period of time as compared to corticotropin. Therefore, therapy may be maintained with less frequent administration.

The long-term administration produces the same effects as those produced by cortisone, cortisol and their synthetic analogues. In addition, there is also hypertrophy and hyperplasia of the adrenal cortex, in contrast to the effect of the exogenous corticoids.

Indications And Clinical Uses :

Adrenal Function Test: The assessment of adrenocortical function based on its response to exogenous ACTH is well established. Nuki, G., et al. (1969) found that there was no significant difference in plasma 11-hydroxycorticosteroid response over 4 hours after a cosyntropin infusion or a single i.m. injection of 1 mg of depot cosyntropin in a group of patients with varying degrees of adrenocortical insufficiency secondary to corticosteroid therapy; suggesting its use to test for adrenocortical insufficiency without recourse of i.v. infusion, which is frequently unpleasant for both patient and clinician. Grant, J.K. (1969) found that the speed of response in the first 20 to 30 minutes is also virtually the same after cosyntropin i.v. as after cosyntropin depot i.m.; reasonably inferring that, except perhaps in states of extreme collapse, little advantage is to be gained in speed of response by giving cosyntropin (short acting) i.v. rather than cosyntropin depot i.m.

Galvao-Teles, A., et al. (1971) proposed as a test of adrenal function that plasma-cortisol be estimated before and 4 to 6 hours after an i.m. injection of 1 mg Synacthen Depot, generally recommended to be given at about 10 a.m. The results may be interpreted as shown in Table I.

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Table I--Synacthen Depot

Interpretation of Plasma Cortisol Levels and Urinary Free Cortisol Excretion after injection of 1 mg Synacthen Depot

Normal Subjects Steroid Treated or Hypopituitary Patients with Abnormal Reserve:

Moderately Impaired Severely Impaired Addisonian Subjects

Plasma-cortisol* 4-6 h

after injection

(µg«100 mL): ³ 35 20-35 <20 <10

(nmol«L): ³ 0.97 0.55-0.97 <0.55 <0.28

Urinary-free cortisol

1st day (µg«day): >700 -- <350 <150

(nmol«L): >19.3 -- <9.66 <4.14

2nd day (µg«day): Less than 1st day -- More than 1st day <150

(nmol«L): -- -- -- <4.14

* By specific method; add one-third if plasma 11 OHCS is measured.

In hypoadrenal subjects, a further sample at 12 to 16 hours is indicated. Intermediate responses may then be clarified by measuring plasma-cortisol after 3 further injections of cosyntropin depot at 48 hour intervals during which period secondary hypoadrenalism may be expected to show recovery. The response to the first injection indicates the extent of adrenal atrophy or destruction, and that to the subsequent injections its recoverability.

Synacthen Depot offers two advantages: first, the longer duration of action might help to provide stronger adrenal stimulation; second, the delay in response to corticotropin in cases of secondary adrenal atrophy which can be shown by prolonged corticotropin stimulation might be elicited by a single injection of Synacthen Depot.

Performance of Adrenal Function Tests:

1. The 30 Minute Synacthen Depot Screening Test: Preparation: The subject need not be fasted. The procedure should be started at about 10:00 a.m. and can be performed as an out-patient procedure.

Procedure: i) A 5 to 7 mL blood sample is taken for determination of plasma cortisol levels at time 0. This will serve as a base against which to compare later values. ii) 1 mg of Synacthen Depot is given by i.m. injection immediately after the blood sample has been taken. iii) A further 5 to 7 mL blood sample is taken exactly 30 minutes after the injection.

Note: Some clinicians take an additional sample 45 to 60 minutes after the injection (in case the 30 minute sample is lost or the assay is invalid for any reason).

Interpretation of Results: In normal subjects the plasma cortisol level at 30 minutes reaches at least 20 µg«100 mL (0.55 nmol«L) with an increment which exceeds 7 µg«100 mL (0.19 nmol«L).

Note: This simple procedure should be used only for screening purposes with any abnormal results requiring confirmation by more prolonged ACTH stimulation. However, a normal response does exclude primary adrenocortical insufficiency, and may also be of value in the serial assessment of adrenocortical function in patients who are, or were, receiving corticosteroid therapy.

2. The 5-Hour Synacthen Depot Test: Preparation: The subject need not be fasted. The procedure should be started at about 10:00 a.m., at least 30 minutes after the insertion of an indwelling needle.

Procedure: i) A 5 to 7 mL blood sample is taken for determination of plasma cortisol levels at time 0. This will serve as a base against which to compare later values. ii) 1 mg of Synacthen Depot is given by i.m. injection immediately after the blood sample has been taken. iii) Further samples are taken after 0.5, 1, 2, 3, 4 and 5 hours for plasma cortisol assay. This assay of several samples avoids a single, possibly inaccurate result which might lead to an erroneous conclusion.

Note: The amount of Synacthen Depot used exceeds the amount required to induce a maximum adrenocortical response, ensuring an accurate assessment of the reserve capacity of the adrenal cortex.

Interpretation of Results: In normal subjects, plasma cortisol levels more than double in the first hour, and then rise more slowly. After 5 hours normal values lie within the range of 37 to 66 µg«100 mL (1.02 1.82 nmol«L).

3. The 3 Day Synacthen Depot Test: Preparation: For procedure A, hospitalization is not required, nor does the patient need to be fasted. Admission to hospital is usually required for procedure B, however, the patient can eat a normal diet and remain ambulant during his in patient stay.

Procedure A: A 30 minute Synacthen Depot test (see section on 30 Minute Synacthen Depot Test) is performed at 9:00 a.m. on day 1. The patient then receives 1 mg of Synacthen Depot injected i.m. on days 2 and 3. On day 4 a second 30 minute Synacthen Depot test is performed at 10:00 a.m.

Procedure B: Urinary cortisol levels are determined on complete 24 hour collections for 5 consecutive days. The first 2 days serve as a control period. Starting on day 3 the patient is given, once daily, i.m. injections of 1 mg Synacthen Depot. See Table II.

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Table II--Synacthen Depot

The 3-Day Synacthen Depot Test: Procedure B

Day 1 Day 2 Day 3 Day 4 Day 5

Daily Urinary Cortisol Determinations

1 mg i.m. daily synacthen Depot at 9:30am

Interpretation of Results: Note: Prolonged ACTH stimulation tests offer advantages over the shorter tests only in differentiating between primary and secondary adrenocortical insufficiency. No response is found in patients with the primary type (Addison's disease) whereas, with prolonged stimulation, in the great majority of patients there is a marked but delayed corticosteroid response in secondary adrenal atrophy. Procedure A provides this information, i.e. a marked improvement in the second 30 minute Synacthen Depot test is consistent with secondary adrenocortical insufficiency whereas no improvement is found in the primary type. As concerns procedure B, in normal subjects, urinary cortisol excretion at least doubles on the first day of Synacthen Depot stimulation (i.e. day 3) and continues to increase during the remainder of the test.

Caution: The administration of ACTH for 3 consecutive days may rarely cause sodium and water retention with the risk of edema while the marked and prolonged increase in circulating corticosteroid levels, that may occur in patients with bilateral adrenal hyperplasia, can cause a severe exacerbation of the symptoms of Cushing's syndrome. On extremely rare occasions, adrenal crisis has supervened during prolonged ACTH stimulation in patients with marked adrenal insufficiency. For this reason, some clinicians give 1 mg of dexamethasone daily through the 3 days on which Synacthen Depot is given to provide steroid cover. This does not interfere with the test.

Synacthen Depot has been used in the following: Collagen Diseases: acute rheumatic fever; rheumatoid arthritis; lupus erythematosus; periarteritis nodosa; psoriatic arthritis; scleroderma; rheumatoid spondylitis; Still's disease.

Dermatologic Diseases: exfoliative dermatitis; dermatomyositis; pemphigus.

Endocrine Diseases: panhypopituitarism.

Eye Diseases: choroiditis; conjunctivitis; iritis; keratitis; optic neuritis; sympathetic ophthalmia; uveitis.

Hemolytic Diseases: acquired hemolytic jaundice.

Other Diseases: nephrotic syndrome; ulcerative colitis; Bell's palsy; acute exacerbations of multiple sclerosis, and as adjuvant treatment in cases of acute gout.

Contra-Indications:

Known or suspected hypersensitivity to cosyntropin and or ACTH of animal origin or to any of the excipients of Synacthen Depot; pregnancy and lactation; untreated bacterial, fungal and viral infections; Cushing's syndrome; refractory congestive heart failure; active or latent peptic ulcer; acute psychosis; primary adrenocortical insufficiency; adrenogenital syndrome.

In view of the increased risk of anaphylactic reactions, Synacthen Depot must not be employed to treat asthma or other allergic affections. Since Synacthen Depot contains benzyl alcohol, it is contraindicated in neonates (especially premature infants), in whom benzyl alcohol can cause severe poisoning.

Warnings in Clinical States:

Synacthen Depot must not be given i.v.

In rare cases, particularly in patients subject to asthma and«or other forms of allergy, severe anaphylactic reactions may occur. Such reactions set in usually within 30 minutes after administration.

If Synacthen Depot is used in any of the following conditions, the risks should be weighed against the possible benefits: non-specific ulcerative colitis; diverticulitis; recent intestinal anastomosis; renal insufficiency; hypertension; thromboembolic tendencies; acute or chronic infections, especially varicella or vaccinia; exanthematous and fungal diseases, osteoporosis; and myasthenia gravis.

Precautions:

Before employing Synacthen Depot, the physician must ascertain whether the patient is suffering from an allergic disorder (especially asthma) or is susceptible in general to allergies (see Contraindications and Warnings). The physician should also enquire whether the patient has been treated with ACTH preparations in the past, and, if so, make sure that the treatment gave rise to no hypersensitivity reactions (see Contraindications).:

Allergic reactions may occur in response to Synacthen Depot, which tend to be more severe in patients susceptible to allergies (especially asthma) (see Contraindications). Because of the possibility of an allergic reaction occurring with Synacthen Depot, the injection should be given under medical supervision and the patient kept under observation for about 1 hour. Self-injection by patients is not recommended. Should any prodromal signs occur, stop further treatment. Allergic reactions of this type include: marked redness and pain at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushings, severe malaise, dyspnea, or angioneurotic edema or Quincke's edema. If local or systemic hypersensitivity reactions occur during or after an injection, treatment with cosyntropin must be discontinued and all use of ACTH preparations avoided in the future.

Treatment of Anaphylactic Reactions: Severe anaphylactic reactions usually can be avoided by discontinuing the use of the drug at the earliest sign of local or systemic hypersensitivity. In the rare event of a serious incident occurring despite these precautions, initiate the following emergency measures as treatment for shock: Initial treatment or for less severe reactions: 0.3 to 0.5 mL s.c. or i.m. of a 1 mg«mL aqueous solution of epinephrine. For more severe or life threatening reactions, or if no response to s.c. or i.m. route: 1 to 5 mL i.v. slowly of a 1 mg«mL aqueous epinephrine solution diluted in 10 mL physiologic saline. As well, consider administering a large i.v. dose of a corticosteroid, e.g. hydrocortisone or methylprednisolone.

Prolonged repeated cosyntropin administration may increase the risk of hypersensitivity reaction.

The blood pressure and weight should be carefully observed. Urinalysis should be done at intervals; if sugar is present the fasting blood glucose should be determined. Salt and water retention in response to Synacthen Depot can often be avoided or eliminated by prescribing a low-sodium diet; diuretics may be employed when strict sodium restriction is impossible.

Potassium supplement should be administered in cases of prolonged use.

Psychological disturbances such as euphoria, depression, insomnia, psychosis, mood swings, personality changes may occur during therapy. Existing emotional disorders or psychoses may be aggravated.

Prolonged use of cosyntropin may be associated with development of posterior subcapsular cataracts and glaucoma.

Infections must be treated simultaneously with appropriate antibiotics; the signs and symptoms of inflammation may be masked by the anti-inflammatory effects of cortisol produced by the over-active adrenal glands.

Vaccination: Patients on therapy with cosyntropin should not be vaccinated against smallpox. If other immunization procedures are considered, these should be undertaken with caution because of decrease in antibody response and possible hazard of neurological complications.

Surgery: Patients who are subjected to the stress of surgical operations or trauma while being treated, or within 1 year after treatment has been terminated, should have their Synacthen Depot therapy augmented or reinstated and continued for the duration of the stress period and immediately following it. In stressful conditions, additional use of rapidly acting corticosteroids may be required.

Although the action of cosyntropin is similar to that of exogenous adrenocortical steroids, the quantity of endogenous corticosteroids produced by the adrenal glands may be variable.

The lowest effective dose of cosyntropin should be used to control the condition under treatment. When reduction of the dosage is indicated, this should be gradual. Relative insufficiency of the pituitary-adrenal axis is induced by prolonged administration, therefore gradual reduction of cosyntropin dosage is essential. On discontinuation of therapy this type of insufficiency may persist for several months. During this period in case of stressful conditions appropriate adrenocortical therapy should be considered.

It is advisable to verify the adrenal responsiveness before and during cosyntropin therapy.

Patients with Special Diseases and Conditions: Patients already receiving medication for diabetes mellitus or for moderate to severe hypertension must have the dosage of their medication readjusted if treatment with Synacthen Depot is instituted.

An enhanced effect of corticotropin therapy has been observed in patients with hypothyroidism and in those with cirrhosis of the liver.

Synacthen Depot should be used cautiously in patients with ocular herpes simplex owing to possible corneal perforation.

Synacthen Depot may activate latent amoebiasis. It is therfore 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.

Children: Provided the dosage is carefully individualized Synacthen Depot is unlikely to inhibit growth in children. Nevertheless, in children undergoing long-term treatment, growth should be monitored.

In infants and small children treated with Synacthen Depot, echocardiographic recordings should be made regularly, because during long-term treatment with high doses reversible myocardial hypertrophy may occur.

Synacthen Depot is contraindicated in neonates.

Adverse Reactions:

:Allergic reaction may develop (see Contraindications and Warnings) which in rare instances can lead to life-threatening anaphylactic shock. In rare cases the benzyl alcohol contained in Synacthen Depot may also give rise to hypersensitivity reactions.

In infants and small children treated over a prolonged period with high dosages, reversible myocardial hypertrophy may occur in isolated instances.

Fluid and Electrolyte Disturbances: sodium retention, fluid retention, potassium loss, hypokalemic alkalosis, calcium loss.

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

Gastrointestinal: peptic ulcer with possible perforation and hemorrhage, pancreatitis, abdominal distension, ulcerative esophagitis.

Dermatologic: impaired wound healing, thin fragile skin, petechiae and ecchymoses, facial erythema, increased sweating, suppression of skin test reactions, acne, hyperpigmentation.

Cardiovascular: hypertension, necrotizing angiitis, congestive heart failure.

Neurological: convulsions, increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment; headache; vertigo; psychic changes.

Endocrine: menstrual irregularities; development of Cushingoid state; suppression of growth in children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; decreased carbohydrate tolerance; hyperglycemia; manifestations of latent diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in diabetics; hirsutism.

Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos.

Metabolic: negative nitrogen balance due to protein catabolism.

Allergic: especially in patients with allergic responses to proteins manifesting as dizziness, nausea and vomiting, anaphylactic shock, skin reactions.

Miscellaneous: Increased susceptibility to infection; abscess; thromboembolism; weight gain; increased appetite; leukocytosis; prolonged ACTH may result in antibodies and loss of stimulatory effect.

Symptoms And Treatment Of Overdose :

OverdoseSymptoms: Edema, hypertension or signs of excessive adrenocortical activity (Cushing's syndrome) during therapy usually indicate overdosage. In such cases the dosage should be reduced, frequency of administration decreased (i.e. to 5 to 7 days) or the drug withdrawn according to the severity of the condition.Treatment

Treatment: There is no known antidote for corticotropin. Toxic effects should be treated symptomatically.

Dosage And Administration:

Test of Adrenal Function: 1 mg Synacthen Depot, injected i.m. at about 10 a.m. Plasma 11-hydroxycorticosteroids to be measured before and 4 to 6 hours after the injection. For interpretation of results, and further measurement and caution in certain cases, refer to Indications.

Dosage for Other Clinical Disorders: In general, the correct dose is the smallest one given at the longest possible interval necessary to produce control of the clinical disorder.

The average dose is 0.5 to 1 mg i.m. twice a week, tailoring the dose according to the individual requirements. In acute cases, or after prolonged steroid therapy, 1 mg i.m. daily for 3 days. However, the interval should be extended as soon as an adequate response is obtained.

Once the acute manifestations have subsided, or for chronic conditions, the dose should be adjusted according to the patient's needs. Some may be best maintained on a dose of 0.5 to 1 mg every 2 or 3 days while others may respond better to 2 mg at weekly, or even longer intervals.

Based on a number of clinical studies, the dosage schedule in Table III is suggested for babies and children.

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Table III--Synacthen Depot

Dosage Schedule for Babies and Children

Age Initial Dosage Maintenance Dosage

Under 1 year 0.25 mg«day 0.25 mg every

2nd day

1 to 6 years 0.25 to 0.5 mg«day 0.25 to 0.5 mg

every 2 to 8 days

6 to 15 years 0.5 to 1 mg«day 0.25 to 1 mg

every 2 to 8 days

Route of administration: The preferred route of administration is by i.m. injection, slowly and deeply into the gluteal region.

The ampuls should be slightly shaken until the suspension shows a uniform appearance.

Transferring from Corticoids: Administer 1 mg Synacthen Depot daily to elicit full adrenal response. At the same time withdraw the steroid gradually, reducing by a quarter the original dose on successive days. Once the steroid has been withdrawn, adjust Synacthen Depot dosage to individual patient's requirements.

Transferring from ACTH of Animal Origin: 1 mg of Synacthen has approximately the same corticotrophic activity as 100 IU of ACTH (as defined in the 3rd International Working Standard). This equivalence is not, however, valid for depot preparations since the effect of Synacthen Depot lasts appreciably longer than ACTH gel and considerably longer than ACTH in carboxymethyl cellulose. To transfer a patient receiving, for example, 40 units ACTH gel daily, give 0.5 mg Synacthen Depot i.m. instead on alternate days. The response should then be assessed and the dosage adjusted, preferably by lengthening the interval between injections.

Availability And Storage:

Availability And Storage:

Each ampul of milky-white, sterile suspension contains: cosyntropin 1 mg as zinc hydroxide complex. Nonmedicinal ingredients: benzyl alcohol, sodium chloride, sodium hydroxide (to adjust pH), disodium phosphate dodecahydrate and sterile water for injection. Alcohol: 1 % w«v. Sodium: <1 mmol (1.13 mg)«mL. Bisulfite-, gluten-, lactose-, parabens- and tartrazine-free. Cartons of 1 ampul. Store in a refrigerator (2 to 8°C). Protect from light.