Depo-Medrol

MGPC (myristyl-gamma-picolinium chloride) formulation This product is intended for single use only. After the required dose has been administered, any remaining suspension must be discarded. Although crystals of adrenocortical steroids in the skin suppress inflammatory reactions, their presence may lead to disintegration of cellular elements and to physicochemical changes in the underlying connective tissue. The resulting, infrequent dermal and/or subdermal changes may produce depressions in the skin at the injection site. The degree of this reaction varies with the amount of adrenocortical steroid administered. Complete regeneration usually occurs within several months or after absorption of all the steroid crystals. To minimise the incidence of dermal and cutaneous atrophy, care must be taken not to exceed the recommended injection doses. Wherever feasible, multiple small injections into the lesion are preferable. Intrasynovial and intramuscular injection techniques also require care to avoid injection into, or leakage of, the material into the dermis. Owing to the high incidence of subcutaneous atrophy, injection into the deltoid muscle should be avoided. DEPO-MEDROL must not be administered by any route other than those listed in section 4.1. It is absolutely essential that correct administration techniques be used for DEPO-MEDROL to ensure proper drug action in the body. Serious adverse reactions have been reported in association with the intrathecal/epidural route of administration (see section 4.8 Adverse reactions). Appropriate steps must be taken to avoid intravascular injection. Special warnings and precautions Intrasynovial injection of a corticosteroid may produce systemic as well as local effects. To exclude an infectious process, examination of any joint fluid present is necessary to rule out the presence of micro-organisms. Marked joint pain together with swelling, restricted joint motion, fever, and malaise are suggestive of septic arthritis. If these signs persist and a diagnosis of sepsis is confirmed, appropriate antibiotic therapy must be instituted. Local injection of a steroid into an infected joint is to be avoided, as is the administration of steroids into unstable joints. Aseptic technique is mandatory to prevent contamination. It should be borne in mind that absorption of the active substance is slower following intramuscular administration. Immunosuppressive effects/increased susceptibility to infection Corticosteroids may increase susceptibility to infection, may mask some signs of infection, may exacerbate existing infections, may increase the risk of reactivation or exacerbation of latent infections, and new infections may emerge during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. In patients treated with corticosteroids alone or in combination with other immunosuppressants that affect cellular or humoral immunity, or neutrophil function, any viral, bacterial, fungal, or parasitic infection may occur at any anatomical site. These infections may be mild, but may also be severe and at times fatal. The frequency of infectious complications increases with increasing doses of corticosteroids. Monitor for the development of infection and, if necessary, consider withdrawal of corticosteroids or dose reduction. For local effect in acute infections, administration into synovial, bursal, or tendon sheath sites is not recommended. Persons taking medicines that suppress the immune system are more susceptible to infections than healthy individuals. For example, chickenpox and measles can have a more serious, or even fatal, course in immunocompromised children or in adults receiving corticosteroids. Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the response to such vaccines may be diminished. Indicated immunisation procedures may be undertaken in patients receiving non-immunosuppressive doses of corticosteroids. The use of corticosteroids in active tuberculosis must be restricted to cases of fulminant or disseminated tuberculosis in which the corticosteroid is used in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is required, as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Kaposi's sarcoma has been reported in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission of the disease. The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with persistent septic shock who exhibit adrenal insufficiency. Nevertheless, their routine use in septic shock is not recommended. A systematic review of short-course, high-dose corticosteroids did not support their use. However, meta-analyses and reviews suggest that longer courses (5–11 days) of low-dose corticosteroids may reduce mortality, particularly in patients with vasopressor-dependent septic shock. Effects on the immune system Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautions should be taken before administration, especially when the patient has a history of allergy to any medicinal product. Effects on the endocrine system In patients on corticosteroid therapy who are subjected to unusual stress, an increased dose of rapid-acting corticosteroids is indicated before, during, and after the stressful situation. Pharmacological doses of corticosteroids administered for prolonged periods may produce suppression of the hypothalamic–pituitary–adrenal (HPA) axis (secondary adrenocortical insufficiency). The degree and duration of resultant adrenocortical insufficiency vary among patients and depend on dose, frequency, time of administration, and duration of glucocorticoid therapy. This effect can be minimised by alternate-day administration. If glucocorticoids are withdrawn abruptly, acute adrenal insufficiency leading to a fatal outcome may occur. Drug-induced secondary adrenocortical insufficiency may therefore be minimised by gradual dose reduction. This type of relative insufficiency may persist for months after discontinuation of therapy; hormonal therapy should therefore be reinstituted in any stressful situation that arises during this period. A "steroid withdrawal syndrome", apparently unrelated to adrenocortical insufficiency, may also occur on cessation of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to a low corticosteroid level. Because glucocorticoids can worsen the condition of patients with Cushing's syndrome, the administration of glucocorticoids in such patients is not recommended. The effect of corticosteroids is enhanced in patients with hypothyroidism. Metabolism and nutrition disorders Corticosteroids, including methylprednisolone, can raise blood glucose levels, worsen pre-existing diabetes mellitus, and predispose patients on long-term corticosteroid therapy to diabetes mellitus. Psychiatric effects Mental disturbances may appear during corticosteroid therapy, including euphoria, insomnia, mood swings, personality changes, and severe depression and frank psychotic manifestations. Exacerbation of pre-existing emotional instability or psychotic tendencies may also occur. Potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions resolve following dose reduction or withdrawal, although specific treatment may be necessary. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is not known. Patients/caregivers should be encouraged to seek medical advice if any psychological symptoms develop, particularly if depressed mood or suicidal ideation is suspected. Patients/caregivers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose reduction/withdrawal of systemic steroids. Effects on the nervous system Corticosteroids should be used with caution in patients with seizure disorders. Corticosteroids should be used with caution in patients with myasthenia gravis. (See also myopathy under Musculoskeletal effects.) Cases of epidural lipomatosis have been reported in patients taking corticosteroids, typically with long-term use at high doses. Effects on the eyes Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, referral to an ophthalmologist should be considered for evaluation of possible causes, which may include cataract, glaucoma, or rare diseases such as central serous chorioretinopathy (CSCR), which has been reported after systemic and topical use of corticosteroids. Central serous chorioretinopathy may lead to retinal detachment. Prolonged use of corticosteroids may produce posterior subcapsular and nuclear cataracts (especially in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerve. The development of secondary ocular fungal and viral infections may be enhanced in patients receiving glucocorticoids. In patients with ocular herpes simplex, corticosteroids should be used with caution because of possible corneal perforation. Effects on the cardiovascular system Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidaemia and hypertension, may render treated patients with existing cardiovascular risk factors more susceptible to additional cardiovascular events when these corticosteroids are administered in high doses and over prolonged periods. Accordingly, corticosteroids should be used judiciously in such patients, and attention should be given to risk modification and to additional cardiac monitoring if needed. Systemic corticosteroids should be used with caution, and only when strictly necessary, in cases of congestive cardiac failure. Vascular effects Thrombosis, including venous thromboembolism, has been reported with corticosteroid use. Corticosteroids should therefore be used with caution in patients who have, or may be predisposed to, thromboembolic disorders. Corticosteroids should be used with caution in patients with hypertension. Effects on the gastrointestinal system High doses of corticosteroids may induce acute pancreatitis. There is no general consensus as to whether corticosteroids per se are responsible for peptic ulcers occurring during therapy. Glucocorticoid therapy may mask the symptoms of peptic ulcer, so that perforation or haemorrhage may occur without significant pain. Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction, or pancreatitis. In combination with non-steroidal anti-inflammatory drugs (NSAIDs), there is an increased risk of developing gastrointestinal ulceration. Corticosteroids should be used with caution in patients with non-specific ulcerative colitis if there is a probability of impending perforation, abscess, or other pyogenic infection; in patients with diverticulitis, fresh intestinal anastomoses, or active or latent peptic ulcer. Hepatobiliary effects Hepatobiliary disorders have been reported, the majority of which were reversible upon discontinuation of therapy. Appropriate monitoring is therefore required. Effects on the musculoskeletal system Acute myopathy has been reported with the use of high doses of corticosteroids, most often in patients with disorders of neuromuscular transmission (e.g. myasthenia gravis) or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking agents (e.g. pancuronium). This acute myopathy is generalised, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after discontinuation of corticosteroids may take weeks to months. Osteoporosis is a common but infrequently recognised adverse effect associated with long-term use of high doses of glucocorticoids. Effects on the liver and biliary tract Drug-induced liver injury, including acute hepatitis or elevated hepatic enzymes, may follow cyclical pulse intravenous administration of methylprednisolone (usually at an initial dose of ≥ 1 g/day). Rare cases of hepatotoxicity have been reported. Time to onset may be several weeks or longer. In most reported cases, the adverse reactions resolved on discontinuation of treatment. Appropriate patient monitoring is therefore required. Renal and urinary disorders Caution is required in patients with systemic sclerosis owing to an increased incidence of scleroderma renal crisis observed with corticosteroids, including methylprednisolone. Corticosteroids should be used with caution in patients with renal insufficiency. No dose adjustment is required in renal failure. Methylprednisolone is dialysable. Investigations Moderate and high doses of hydrocortisone or cortisone may cause elevation of blood pressure, sodium and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic glucocorticoid derivatives except when used in high doses. Dietary salt restriction and potassium supplementation may be necessary in patients so treated. All corticosteroids increase calcium excretion. Injury, poisoning, and procedural complications Systemic corticosteroids are not indicated for and should not be used to treat traumatic brain injury. A multicentre study revealed an increase in mortality at 2 weeks and at 6 months post-injury in patients administered methylprednisolone sodium succinate compared with patients receiving placebo. A causal association with methylprednisolone sodium succinate treatment has not been established. Other Because complications of glucocorticoid therapy depend 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. Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic adverse effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse effects, in which case patients should be monitored for systemic corticosteroid adverse effects (see section 4.5). Acetylsalicylic acid and non-steroidal anti-inflammatory drugs should be used with caution in conjunction with corticosteroids. Co-administration of oral anticoagulants and methylprednisolone may increase the risk of bleeding. Diminished response to oral anticoagulants has also been reported. Frequent monitoring of prothrombin time (INR) is recommended in patients treated with vitamin K antagonists, especially at the initiation of methylprednisolone therapy or during dose adjustment (see section 4.5). Phaeochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should be administered to patients with suspected or identified phaeochromocytoma only after an appropriate risk/benefit evaluation. Post-marketing, tumour lysis syndrome (TLS) has been reported in patients with malignancies, including haematological malignancies and solid tumours, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk for TLS, such as those with cancers having a high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be closely monitored and appropriate precautions taken. Thyrotoxic periodic paralysis (TPP) may occur in patients with hyperthyroidism and methylprednisolone-induced hypokalaemia. A suspicion of TPP should be considered in patients treated with methylprednisolone who present with signs or symptoms of muscle weakness, particularly in those with hyperthyroidism. If TPP is suspected, blood potassium levels must be monitored immediately and adjusted appropriately to ensure that normal blood potassium levels are restored. Use in children During long-term administration in children, growth and development must be carefully monitored. Growth may be suppressed in children receiving long-term, daily, divided-dose glucocorticoid therapy, and the use of such a regimen should be restricted to the most urgent indications. Alternate-day glucocorticoid therapy usually avoids or minimises these adverse effects. Infants and children on prolonged corticosteroid therapy are at increased risk of raised intracranial pressure. High doses of corticosteroids may produce pancreatitis in children. Depo-Medrol contains less than 1 mmol (23 mg) of sodium per millilitre of suspension; that is to say, it is essentially "sodium-free".