DEXARELIEF
-
Chemical Name:
Dexamethasone -
Therapeutic Category:
Anti-inflammatory drugs -
Pharmacologic Category:
Corticosteroid -
Pharmaceutical Form:
Ampoule -
Composition:
Dexamethasone Phosphat 8mg/2ml
DEXARELIFE
Ampoule
Dexamethasone Phosphate (as Sodium)
Solution for IM/IV ,intra synovial and soft tissues Injection
1.COMPOSITION:
DEXARELIEF – ampoule : Each 2mL ampoule contains: Dexamethasone Phosphate (as Sodium) 8mg (4mg/1ml).
Excipients:
-Sodium Citrate.
-Creatinine.
-Hydrochloride acid or Sodium hydroxide (for adjust the PH).
2.PHARMACOLOGY:
Mechanism of action: Dexamethasone is a synthetic adrenocorticosteroid with glucocorticoid activity. It is one of the most active glucocorticoids, being about 25 to 30 times as potent as hydrocortisone. Unlike hydrocortisone, dexamethasone has little if any mineralocorticoid activity.
Dexamethasone has anti-inflammatory and immunosuppressant activity. Glucocorticoids prevent the development of the inflammatory response, i.e. redness, swelling, tenderness. They also inhibit capillary dilation and phagocytosis and appear to prevent the hypersensitivity responses which occur after antigen-antibody reactions.
Dexamethasone suppresses the release of adrenocorticotrophic hormone (ACTH) from the pituitary, resulting in inhibition of endogenous corticotrophin secretion.
Except for its use in the treatment of adrenal insufficiency, dexamethasone does not cure disease. Rather, the anti-inflammatory and immunosuppressant actions of dexamethasone suppress the symptoms associated with the disease.
Pharmacokinetics: Dexamethasone phosphate (as sodium) is absorbed rapidly following intramuscular or intravenous injection. Intramuscular injections of dexamethasone phosphate give maximum plasma concentrations of dexamethasone at 1 hour. The biological half-life of dexamethasone is about 190 minutes.
In the circulation, small amounts of dexamethasone are bound to plasma proteins. Synthetic corticosteroids such as dexamethasone are less extensively protein bound and more slowly metabolised than hydrocortisone. Dexamethasone penetrates into tissue fluids and cerebrospinal fluids. Metabolism occurs in most tissues, but primarily in the liver. The inactive metabolites are excreted in the urine, mainly as glucuronides and sulphates, but also as unconjugated metabolites. Small amounts of unchanged drug are also excreted in the urine. Up to 65% of a dose of dexamethasone is excreted in the urine within 24 hours.
3.INDICATIONS:
Dexamethasone is indicated for therapy of the following diseases:
- Collagen diseases: Systemic lupus erythematosus, polyarteritis nodosa, dermatomyositis, giant cell arteritis, acute rheumatic carditis.
- Pulmonary disorders: Status asthmaticus, chronic asthma, sarcoidosis, respiratory insufficiency.
- Blood disorders: Leukaemia, idiopathic thrombocytopaenic purpura in adults, acquired haemolytic anaemia.
- Rheumatic diseases: Rheumatoid arthritis, osteoarthritis.
- Skin diseases: Psoriasis, erythema multiforme, pemphigus, neutrophilic dermatitis, localized neurodermatitis, exfoliative dermatitis, sarcoidosis of skin, severe seborrhoeic dermatitis, contact dermatitis.
- Gastrointestinal disorders: Ulcerative colitis, regional enteritis.
- Oedema: Cerebral oedema associated with primary or metastatic brain tumours, neurosurgery or stroke, oedema associated with acute non-infectious laryngospasm (or laryngitis).
- Eye disorders: Allergic conjunctivitis, keratitis, allergic corneal marginal ulcers, chorioretinitis, optic neuritis, anterior ischaemic optic neuropathy.
- Neoplastic states: Cerebral neoplasms, hypercalcaemia associated with cancer, leukaemias and lymphomas in adults, acute leukaemia in children.
- Endocrine disorders: Adrenal insufficiency.
* Preoperative and postoperative support: Dexamethasone may be used in any surgical procedure when the adrenocortical reserve is doubtful. This includes the treatment of shock due to excessive blood loss during surgery as an adjunct.
* Shock: Dexamethasone may be used as an adjunct in the treatment of shock. Dexamethasone should not be used as a substitute for normal shock therapy.
* Replacement therapy - adrenocortical insufficiency: Dexamethasone supplemented with salt and/or a mineralocorticoid, such as deoxycorticosterone is indicated in:
- Acute adrenocortical insufficiency - Addison's disease, bilateral adrenalectomy;
- Relative adrenocortical insufficiency - Prolonged administration of adrenocortical steroids can produce dormancy of the adrenal cortex. The reduced secretory capacity gives rise to a state of relative adrenocortical insufficiency which persists for a varying length of time after therapy is discontinued.
- Primary and secondary adrenocortical insufficiency.
4.CONTRAINDICATIONS:
Administration of dexamethasone is contraindicated in the following cases:
- Systemic fungal infections, or other systemic infections unless specific anti-infective therapy is given.
- Hypersensitivity to dexamethasone or other corticosteroids or to any component of the injection.
- Administration of live virus vaccines.
- In patients with myasthenia gravis, peptic ulcer, osteoporosis or psychoses.
5.PRECAUTIONS:
- Corticosteroids may mask the symptoms of infection, and therefore should be used with caution in patients with systemic infections. Chicken pox, measles and other infections can have a more serious or even fatal effect in non-immune children or adults on corticosteroids. Immunosuppression is most likely to occur in patients receiving longer term, high dose systemic corticosteroid treatment; however patients receiving moderate doses for short periods, or low doses over a prolonged period, may also be at risk.
- Corticosteroids should be administered with caution to patients with latent tuberculosis or tuberculin reactivity, as reactivation of the disease may occur. These patients should therefore undergo chemoprophylaxis during prolonged corticosteroid therapy.
- Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
- Long term treatment should not be abruptly discontinued, as too rapid withdrawal may lead to drug induced secondary adrenocortical insufficiency. This may be minimised by gradual dosage reduction. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome, including fever, myalgia, arthralgia and malaise.
- Dexamethasone should be used only with extreme caution in patients with diabetes mellitus or in those with a family history of diabetes, infectious diseases, congestive heart failure or recent myocardial infarction, chronic renal failure, diverticulitis, hypertension, keratitis, epilepsy and/or seizure disorder, non-specific ulcerative colitis, fresh intestinal anastomoses, peptic ulcer, osteoporosis, myasthenia gravis receiving anticholinesterase therapy since corticosteroid use may decrease plasma anticholinesterase activity, or in elderly persons.
- Corticosteroids should be used with caution in patients who have had a recent cardiac infarction; in patients with a history of severe disorders particularly of steroid induced psychoses; patients with previous steroid myopathy, liver failure, renal insufficiency, glaucoma; patients with thromboembolic disorders, patients with Duchenne’s muscular dystrophy; Cushing’s disease. Corticosteroids show an enhanced effect in patients with hypothyroidism or cirrhosis.
- Intra-articular injection of corticosteroids may produce systemic as well as local effects. Appropriate examination of any joint fluid present is necessary to exclude a septic process. Local injection of a steroid into an infected site is to be avoided. Corticosteroids should not be injected into unstable joints. Frequent intra-articular injection may result in damage to joint tissues. Patients should be advised strongly of the importance of not overusing joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active.
- During prolonged corticosteroid therapy sodium intake may need to be reduced and calcium and potassium supplements may be necessary. Monitoring of fluid intake and output and daily weight records may give an early warning of fluid retention.
- Prolonged use of corticosteroids may produce subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves.
- Patients and/or carers should be warned that potentially severe psychiatric reactions may occur. Symptoms typically emerge within a few days or weeks of starting treatment.
- Use in Children: Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible and therefore long-term administration of pharmacological doses should be avoided. If prolonged therapy is necessary, treatment should be limited to the minimum suppression of the hypothalamo-pituitary adrenal axis and growth retardation, the growth and development of infants and children should be closely monitored. Treatment should be administered where possible as a single dose on alternate days.
- Use in the elderly: Long-term use in the elderly should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close medical supervision is required to avoid life threatening reactions.
- Use in pregnancy (Category C): Since the possibility of suppression of the adrenal cortex in the newborn baby after long term treatment must be considered, the needs of the mother must be carefully weighed against the risk to the foetus when prescribing corticosteroids. However, the short term use of antepartum corticosteroids for the prevention of respiratory distress syndrome, when warranted, does not seem to pose a risk.
- Use in lactation: Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production or cause other unwanted effects in breastfed infants. Women taking corticosteroids should be advised not to breastfeed.
6.DRUG INTERACTIONS:
- Medicines that induce hepatic enzyme cytochrome P-450 isozyme 3A4 such as barbiturates, phenylbutazone, phenytoin or rifampicin, rifabutin, carbamazepine, primidone and aminoglutethimide may increase the metabolism and thus reduce the effects of corticosteroids. Ephedrine may also increase dexamethasone metabolism.
- Medicines that inhibit hepatic enzyme cytochrome P-450 isozyme 3A4 such as ketoconazole, ciclosporin or ritonavir, antithyroid agents, oestrogens and other oral contraceptives may decrease hepatic metabolism and thus increase the effects of corticosteroids. The dose of corticosteoid may need to be adjusted if oestrogen therapy is commenced or stopped.
- The effects of anticoagulant agents are usually decreased (but may be increased in some patients) if corticosteroids are administered concurrently. Close monitoring of the INR or prothrombin time is recommended.
- The effect of corticosteroids may be reduced for 3-4 days after mifepristone.
- Seizures have reportedly occurred in adult and paediatric patients receiving high dose corticosteroid therapy concurrently with cyclosporin.
- Concurrent administration of dexamethasone with anticoagulants, heparin, streptokinase, urokinase, alcohol or non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin may increase the risk of gastrointestinal ulceration or haemorrhage. Aspirin should be used cautiously in conjunction with conticosteroids in patients with hypothrombinaemia. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
- Potassium loss may occur as a result of dexamethasone administration. Concurrent administration of corticosteroids with potassium depleting diuretics (such as thiazides, frusemide or ethacrynic acid), carbonic anhydrase inhibitors such as acetazolamide or amphotericin B may result in severe hypokalaemia. The activity of digitalis glycosides and nondepolarising neuromuscular blocking agents may be potentiated as a result of glucocorticoid induced hypokalemia. The efficacy potassium supplements and potassium sparing diuretics on serum potassium concentrations may be reduced by concurrent corticosteroid administration. Monitoring of serum potassium concentration is therefore recommended.
- Glucocorticoids may increase blood glucose concentrations. Dosage adjustment of asparaginase and of anti-diabetic agents such as sulphonylureas and insulins may be necessary.
- The growth promoting effect of somatropin may be inhibited.
- There is an increased risk of hypokalaemia if high doses of corticosteroids are given with high doses of salbutamol, salmeterol, terbutaline or formoteral.
- Concurrent use of antacids may decrease absorption of corticosteroids – efficacy may be decreased sufficiently to dosage adjustments in patients receiving small doses of corticosteroids.
Effects on laboratory tests:
- False negative results in the dexamethasone suppression test have been reported in patients being treated with indomethacin or high doses of benzodiazepines or cyproheptadine.
- Corticosteroids may affect a wide range of diagnostic tests. They may affect brain and skeletal imaging using Tc99, by decreasing uptake of Tc99 into cerebral tumours or bone, and may decrease I123 and I131 uptake into the thyroid. Corticosteroids may alter the results of the gonadorelin test for hypothalamic-pituitary-gonadal axis function, affect thyroid function test results, and suppress skin test reactions including tuberculin and histoplasmin skin tests, and patch tests for allergy. Corticosteroids may also affect the nitroblue tetrazolium test for bacterial infection and produce false negative results.
7.ADVERSE EFFECTS:
The following adverse effects have been reported with dexamethasone therapy. Except for allergic reactions, the adverse effects listed have been associated with prolonged therapy and/or high doses.
Endocrine effects: Adrenal suppression, menstrual irregularities, amenorrhoea, development of Cushingoid state, weight gain, secondary adrenocortical and pituitary unresponsiveness particularly in times of stress (e.g. trauma, surgery or illness), decreased carbohydrate tolerance, increased requirements for insulin or oral hypoglycaemic agents in diabetes, development of diabetes mellitus, hyperglycaemia, hirsutism, growth suppression in infancy, childhood and adolescence, increased appetite.
Cardiovascular effects: Thromboembolism, hypertension, polymorphonuclear leucocytosis, neuropathy, vasculitis, impaired myocardial contractility (prolonged treatment), congestive heart failure in susceptible patients, myocardial rupture following recent cardiac infarction, hypertrophic cardiomyopathy in low birth weight infants.
Musculoskeletal effects: Proximal myopathy, osteoporosis, arthropathy, muscular atrophy, muscle weakness, steroid myopathy, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fracture of long bones, avascular osteonecrosis, tendon rupture, myalgia. These may occur as a result of protein catabolism associated with prolonged glucocorticoid therapy.
Ocular effects: Increased intraocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, cataracts, exophthalmos, corneal or scleral thinning, retinopathy of prematurity, enhanced establishment of secondary fungal and viral eye infections.
Dermatological effects: Impaired wound healing, hirsutism, skin atrophy, allergic dermatitis, urticaria, erythema, thin fragile skin, telangiectasia, petechiae and ecchymoses, increased sweating, burning or tingling especially in the perineal area (after intravenous injection), angioneurotic oedema, acne, striae, easy bruising.
Gastrointestinal effects: Dyspepsia, nausea, peptic ulcer with possible perforation and haemorrhage, abdominal distension, abdominal pain, increased appetite which may result in weight gain, diarrhoea, acute pancreatitis, perforation of the small or large bowel particularly in patients with inflammatory bowel disease, , ulcerative oesophagitis, oesophageal candidiasis.
Neurological effects: Euphoric side effects, mental disturbances, psychological dependence, depression, insomnia, dizziness, headache, convulsions, increased intracranial pressure with papilloedema in children, usually after treatment withdrawal, vertigo. Aggravation of schizophrenia, aggravation of epilepsy suicidal ideation, mania, delusions, hallucinations, irritability, anxiety and cognitive dysfunction. In adults the frequency of severe psychiatric reactions has been estimated to be 5-6%.
Fluid and electrolyte disturbances: Electrolyte imbalance (retention of sodium and water with oedema and hypertension), potassium loss, hypokalaemic alkalosis, hypocalcaemia.
Metabolic effects: Nitrogen depletion, negative nitrogen and calcium balance due to protein catabolism.
Other effects: allergic reactions, leucocytosis, anaphylactic or hypersensitivity reactions, fatigue, malaise, hiccups.
Hyperpigmentation or hypopigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post injection flare (following intra-articular use).
8.DOSAGE AND ADMINISTRATION:
Dexamethasone Sodium Phosphate Injection may be administered intravenously or intramuscularly for systemic effect, or as an intra-synovial or soft tissue injection for local effect.
Use once only and discard any residue.
Intravenous and intramuscular administration:
Intravenous or intramuscular dosage usually ranges from 0.5 to 24 mg of dexamethasone phosphate daily. The duration of therapy is dependent on the clinical response of the patient and as soon as improvement is indicated, the dosage should be adjusted to the minimum required to maintain the desired clinical response. Withdrawal of the drug on completion of therapy should be gradual.
Shock (of haemorrhagic, traumatic or surgical origin): The usual dose for the treatment of shock is 2 to 6 mg/kg bodyweight as a single intravenous injection. This may be repeated in 2 to 6 hours if shock persists.
An alternative regimen of 20 mg by intravenous injection initially, followed by continuous intravenous infusion of 3 mg/kg bodyweight per 24 hours, has been suggested. If required for intravenous infusion, dexamethasone phosphate may be diluted with glucose or sodium chloride injection.
High dose therapy should be continued only until the patient's condition has stabilised and usually for no longer than 48 to 72 hours.
To avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation of the mixture and if storage is necessary, store solution at 2 to 8°C. Infusion should be completed within 24 hours of preparation of the solution and any residue discarded.
High Dose Schedule:
|
|
Adults
|
Children > 35 kg
|
Children < 35 kg
|
|
Initial Dose
|
50 mg IV
|
25 mg IV
|
20 mg IV
|
|
1st day
|
8 mg IV every 2 hours
|
4 mg IV every 2 hours
|
4 mg IV every 3 hours
|
|
2nd day
|
8 mg IV every 2 hours
|
4 mg IV every 2 hours
|
4 mg IV every 3 hours
|
|
3rd day
|
8 mg IV every 2 hours
|
4 mg IV every 2 hours
|
4 mg IV every 3 hours
|
|
4th day
|
4 mg IV every 2 hours
|
4 mg IV every 4 hours
|
4 mg IV every 6 hours
|
|
5th-8th day
|
4 mg IV every 4 hours
|
4 mg IV every 6 hours
|
2 mg IV every 6 hours
|
|
After 8 days
|
Decrease by daily
reduction of 4 mg
|
Decrease by daily
reduction of 2 mg
|
Decrease by daily
reduction of 1 mg
|
Cerebral oedema: An initial dose of 10 mg intravenously followed by 4 mg intramuscularly every 6 hours until the symptoms of oedema subside (usually after 12 to 24 hours). After 2 to 4 days the dosage should be reduced and gradually stopped over a period of 5 to 7 days. Patients with cerebral malignancy may require maintenance therapy with doses of 2 mg intramuscularly or intravenously 2 to 3 times daily.
High doses of dexamethasone may be used to initiate short term intensive therapy for acute cerebral oedema.
Intra-synovial & soft tissue injections:
Dosage varies with the degree of inflammation and the size and location of the affected area.
Injections may be repeated from once every 3 to 5 days (e.g. for bursae) to once every 2 to 3 weeks
(for joints). Frequent intra-articular injection may result in damage to joint tissues.
|
Site of Injection
|
Dosage
|
|
Large Joints
|
2 mg to 4 mg
|
|
Small Joints
|
800 micrograms to 1 mg
|
|
Bursae
|
2 mg to 3 mg
|
|
Tendon Sheaths
|
400 micrograms to 1 mg
|
|
Soft tissue Infiltration
|
2 mg to 6 mg
|
|
Ganglia
|
1mg to 2 mg
|
9.OVERDOSAGE:
Symptoms: Reports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare. Exaggeration of corticosteroid related adverse effects may occur including hypertension, oedema, peptic ulceration, hyperglycaemia and altered mental state. Anaphylactic or hypersensitivity reactions may occur.
Treatment: No antidote is available. Treatment of overdosage is symptomatic. The dosage should be reduced or the drug withdrawn. Anaphylactic and hypersensitivity reactions may be treated with adrenaline (epinephrine), positive pressure artificial respiration, and aminophylline. The patient should be kept warm and quiet.
10.PACKAGING :
DEXARELIEF – ampoule : A pack of 5 amber glass ampoules of 2 ml.
11.STORAGE CONDITIONS:
Store at temperature below 25°C. Protect from light.
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