Adverse reactions : תופעות לוואי

Adverse Reactions
Local adverse reactions include post-injection flare, and a painless destruction of the joint reminiscent of Charcots arthropathy especially with repeated intra-articular injection.
The incidence of predictable undesirable effects, including hypothalamic-pituitary- adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment. Cases of ruptured tendon have been reported.
Local injection of glucocorticoid may produce systemic effects 
Fluid and Electrolyte Disturbances
Sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalemic alkalosis, hypertension.

Musculoskeletal
Muscle weakness, steroid myopathy, loss of muscle mass (muscular atrophy) , tendon rupture, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fractures of long bones, proximal myopathy .

Gastrointestinal
Peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the intestine particularly in patients with inflammatory bowel disease, pancreatitis, candidiasis , abdominal distension, ulcerative esophagitis.

Dermatological
Impaired wound healing, thin fragile skin, petechiae and ecchymoses, erythema, increased sweating.
Corticosteroids may suppress reactions to skin tests.
Burning or tingling, especially in the perineal area (after I.V.injection).
Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema.

Neurological
A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported.
Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown Convulsions, increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment, vertigo, headache, psychic disturbances, euphoric side effects cerebral palsy in preterm infants.

Endocrine
Menstrual irregularities, amenorrhea, 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, manifestations of latent diabetes mellitus, increased requirements of insulin or oral hypoglycemic agents in diabetics, hirsutism.

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Opthalmological
Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmus, retinopathy of prematurity.

Metabolic
Negative nitrogen balance due to protein catabolism.

Blood/Vascular Disorders :
Thromboembolism, polymorphonuclear           leucocytosis,   neuropathy,     vasculitis, development of Diabetes Mellitus

Effect on Bones and Joints
Osteoporosis, arthropathy, osteonecrosis of femoral and/or humeral heads (aseptic or avascular necrosis).

Cardiovascular
Myocardial rupture following recent myocardial infarction.
Hypertrophic cardiomyopathy in low birth weight infants
Impaired cardiac contractility

Anti-inflammatory and Immunosuppressive effects
Increased susceptibility and severity of infections with suppression of clinical symptoms and signs. Diminished lymphoid tissue and immune response.
Opportunistic infections, recurrence of dormant tuberculosis and decreased responsiveness to vaccination and skin tests.

Other
Anaphylactoid or hypersensitivity reactions, thromboembolism, weight gain, increased appetite, nausea, malaise, hiccups.
The following additional adverse reactions are related to parenteral corticosteroid therapy: rare instances of blindness associated with intra-lesional therapy around the face and head, hyperpigmentation or hypopigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post-injection flare (following intra-articular use) and Charcot-like arthropathy.

Withdrawal Symptoms
Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death.
A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Precautions
Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case, as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including fever, myalgia, arthralgia, and malaise. This may occur in patients even without evidence of adrenal insufficiency.


DEXACORT Forte Injection      22- 1. 2013 RH                    Page 5 of 10 Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by the gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy. Therefore, in any situation of stress occurring during this period, hormone therapy should be reinstituted. If the patient is receiving steroids already, the dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
Corticosteroids have an enhanced effect on patients with hypothyroidism and hepatic cirrhosis.
Corticosteroids should be used with caution in patients with ocular herpes simplex because of possible corneal perforation.
Psychic derangements may appear when corticosteroids are used. These can range from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. In addition, corticosteroids may aggravate existing emotional instability or psychotic tendencies.
Co-administration of thalidomide with dexamethasone phosphate injection should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use.
Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Corticosteroids should be used with caution in non-specific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyogenic infection, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis and myasthenia gravis. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism.
Steroids may increase or decrease motility and number of spermatozoa in some patients.
Growth and development of infants and children receiving prolonged corticosteroid therapy should be carefully observed.
Routine laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray, should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia.

Special Precautions
(see also Contraindications)
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.
 a. Osteoporosis (post-menopausal females are particularly at risk).
b. Hypertension or congestive heart failure.
c. Existing or previous history of severe affective disorders (especially previous steroid psychosis).
d. Diabetes mellitus (or a family history of diabetes).
e. History of tuberculosis, since glucocorticoids may induce reactivation.
f. Glaucoma (or a family history of glaucoma).
g. Previous corticosteroid-induced myopathy.
h. Liver failure.
i. Renal insufficiency.
j. Epilepsy.
k. Gastro-intestinal ulceration.
DEXACORT Forte Injection      22- 1. 2013 RH                   Page 6 of 10 l. Migraine m. Certain parasitic infestations in particular amoebiasis.
n. Incomplete statural growth since glucocorticoids on prolonged administration may accelerate epiphyseal closure o. Patients with Cushing's syndrome
In the treatment of conditions such as tendinitis or tenosynovitis care should be taken to inject into the space between the tendon sheath and the tendon as cases of ruptured tendon have been reported.

Drug Interactions
Dexamthasone/Erythromycin/Indinavir Dexamethasone is a moderate inducer of CYP 3A4.Co-administration of dexamethasone with other drugs that are metabolized by CYP 3A4 (e.g.,indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentrations.
CorticosteroidsCytochrome P450 3A4 {CYP 3 A4} Enzyme Inducers (such as Phenytoin, Primidone, Phenylbutazone Carbamazepine, Phenobarbital, Rifampicin, Rifabutin, Aminoglutethemide ) : Cytochrome P450 3A4 (CYP 3A4) enzyme inducers, such as phenytoin, barbiturates (e.g., phenobarbital), carbamazepine, and rifampin may enhance the metabolic clearance of corticosteroids. resulting in reduced therapeutic effects, that require dosage adjustment of the corticosteroid to achieve the desired response.
Corticosteroids/Ephedrine: Ephedrine may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity, thus requiring an increase in corticosteroid dosage
Corticosteroids/CYP Inhibitors such as Troleandomycin, Ketoconazole Isoniazid, Estrogen or Estrogen-Containing Contraceptives: Concurrent administration may lead to a significant decrease in the clearance of the corticosteroid, through inhibition of its metabolism. Therefore, the dose of the corticosteroid should be titrated to avoid steroid toxicity.
Corticosteroids/Cyclosporine: Concurrent use leads to mutual inhibition of metabolism. It is possible that adverse events associated with individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use. Although the combination is therapeutically beneficial for organ transplants, toxicity may be increased, and should be taken into consideration.
Corticosteroids/Digitalis Glycosides: Concurrent use may increase the possibility of digitalis toxicity associated with hypokalemia.
Corticosteroids/Potassium-depleting Diuretics/Amphotericin B/Carbonic Anhydrase Inhibitors: Concurrent use may cause hypokalemia; serum potassium level should be determined at frequent intervals.
Corticosteroids/Hypoglycemics/Streptozocin/Asparaginase:         Corticosteroids      may increase blood glucose levels; dosage adjustment of the antidiabetic agent is necessary.
Corticosteroids/Anticoagulants: Corticosteroids may alter the response to coumarin anticoagulants. Therefore, caution is recommended when these drugs are used concurrently, especially in patients prone to gastrointestinal ulceration and hemorrhage. Therefore, coagulation indices should be frequently monitored during and after glucocorticoid therapy to maintain the desired anticoagulant effect.
Corticosteroids/Aspirin: Corticosteroids may increase the clearance of chronic high-dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when the steroid is withdrawn. Special caution is required in patients presenting with hypoprothrombinemia.
Corticosteroids/Anticholinesterases: Concurrent administration may antagonise the anticholinesterase effects in myasthenia gravis.


DEXACORT Forte Injection       22- 1. 2013 RH                     Page 7 of 10 Corticosteroids/Potassium Supplements/Potassium-Sparing Diuretics:        Concomitant use of these medications may cause a decrease in serum potassium concentration; monitoring of serum potassium concentration is recommended.
Corticosteroids/Ritodrine: Concurrent use may cause pulmonary edema in the mother. Maternal death has been reported. Therefore, both medications should be discontinued at the first sign of pulmonary edema.
Corticosteroids/ Mexiletine: Concurrent use may accelerate mexiletine metabolism, leading to decreased mexiletine plasma concentration.
Corticosteroids/Somatropin: Concomitant administration may lead to inhibition of the growth response to somatropin. this may occur with daily doses of oral or parenteral corticosteroid (calculated per square meter of body surface) in excess of: 375-563 micrograms/ml for oral dexamethasone
187.5-281.5 micrograms/ml for parenteral dexamethasone
10-15 mg for oral hydrocortisone
5-7.5 mg for parenteral hydrocortisone.
Therefore, it is recommended that these doses of the corticosteroids should not be exceeded during somatropin therapy. If larger doses of the corticosteroids are required, the administration of somatropin should be postponed.
Concurrent use of somatropin with corticotropin is not recommended.
Corticosteroids/ Vaccines, Live Virus or Other Immunizations: Immunizations are not recommended in receiving pharmacologic (immunosuppressant) doses of glucocorticoisteroids because of the increased risk of neurological complications and the possibility of decreased or absent antibody response (see also contraindications, Warnings).

Diagnostic Interference
Blood and urine glucose, and serum cholesterol levels may be increased.
Decreased serum levels of potassium, triiodothyronine (T3), and a minimal decrease of thyroxine (T4) may occur. Thyroid I131 uptake may be decreased.
Corticosteroids may effect the nitroblue-tetrazolium test for bacterial infection and produce false-negative results.
False negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Therefore, DST results should be interpreted with caution in these patients.
Basophil, eosinophil, lymphocyte and monocyte counts may be decreased.
Serum calcium concentrations may be decreased.
In skin tests, including tuberculin and histoplasmin skin tests and patch tests for allergy, reactions may be suppressed, especially with daily administration of large doses of corticosteroids.

Information for Patients
General
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although dose levels do not allow prediction of the onset, type severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

DEXACORT Forte Injection       22- 1. 2013 RH                    Page 8 of 10 Intra-articular injection of a corticosteroid may produce systemic as well as local effects.
Appropriate examination of any joint fluid present is necessary to exclude a septic process.
A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise is suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.
Injection of a steroid into an infected site is to be avoided.
Corticosteroids should not be injected into unstable joints.
Patients should be impressed strongly with the importance of not overusing joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active.
Frequent intra-articular injection may result in damage to joint tissues.
The slower rate of absorption by intramuscular administration should be recognized.
Susceptible patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Pediatric Use: Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully followed.

Dosage and Administration
Notes
Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy. Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage requirements are variable, and must be individualized on the basis of the disease and the response of the patient.

Dexacort Forte Injection, which is indicated for the adjunctive treatment of severe shock, must be given by i.v. administration only.
Reported regimens range from 1-6 mg/kg body weight as a single i.v. injection, to 40 mg initially followed by repeated i.v. injections every 2-6 hours, while shock persists.
Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized, and usually not longer than 48-72 hours.
Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.