Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2020 Publisher: Pfizer New Zealand Ltd, PO Box 3998, Auckland, New Zealand, 1140
Known hypersensitivity to methylprednisolone or any component of the formulation.
Systemic fungal infections.
Intrathecal administration due to its potential for neurotoxicity.
Epidural administration.
Intravenous administration as the product is a suspension.
It MUST NOT be used by the intrathecal, epidural, intravenous or any other unspecified routes.
Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids (see section 4.4, Immunosuppressive Effects/Increased Susceptibility to Infections).
The lowest possible dose of corticosteroid should be used to control the condition under treatment and when reduction in dosage is possible, the reduction should be gradual. 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.
This product is not suitable for multidose use. Following administration of the desired dose, any remaining suspension should be discarded.
While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed.
In order to minimise the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.
Depo-Medrol should not be administered by any route other than those listed under section 4.1. It is critical that, during administration of Depo-Medrol, appropriate technique be used and care taken to assure proper placement of the medicine.
Severe medical events have been reported in association with the contraindicated intrathecal/epidural routes of administration (see section 4.8). Appropriate measures must be taken to avoid intravascular injection.
Due to their suppression of the inflammatory response and immune function, corticosteroids may increase susceptibility to fungal, bacterial and viral infections and their severity. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, they should seek urgent medical attention. Passive immunisation is recommended if nonimmune patients who come into contact with chicken pox. If a diagnosis of chicken pox is confirmed the illness warrants specialist care and urgent treatment.
The immunosuppressive effects of corticosteroids may also result in activation of latent infection or exacerbation of existing infection. Corticosteroids should be used with great care in patients with known or suspected parasitic infections such as strongyloides infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicaemia.
It is important to note that corticosteroids may increase susceptibility to infection, may mask some signs of infection, which may reach an advanced stage before the infection is recognised, and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. Infections with any pathogen, including viral, bacterial, fungal, protozoan or helminthic organisms, in any location in the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Caution must therefore be exercised in patients with HIV/AIDS or diabetes.
Do not use intra-articular, intrabursal or intratendinous administration for local effect in the presence of acute infection.
Depo-Medrol is not recommended for use in patients with septic shock or sepsis syndrome. 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 established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended and a systematic review concluded that short-course, high-dose corticosteroids did not support their use. However, meta-analyses and a review suggest that longer courses (5-11 days) of low-dose corticosteroids might reduce mortality, especially in those with vasopressor-dependent septic shock.
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 methylprednisolone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
Allergic reactions (e.g. angioedema) may occur.
Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions (e.g. bronchospasm) have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug. Allergic skin reactions have been reported apparently related to the excipients in the formulation. Rarely has skin testing demonstrated a reaction to methylprednisolone acetate, per se.
In patients on corticosteroid therapy (or those who have discontinued treatment but continue to experience symptoms of adrenal insufficiency) who are subjected to unusual stress such as intercurrent illness, trauma or surgery, increased dosage (or reinstitution) of rapidly acting corticosteroids may be required.
Pharmacologic doses of corticosteroids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration, and duration of glucocorticoid therapy. This effect may be minimised by use of alternate-day therapy.
In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly. Therefore, withdrawal of corticosteroid should always be gradual.
Symptoms of adrenal insufficiency include: malaise, muscle weakness, mental changes, muscle and joint pain, desquamation of the skin, dyspnoea, anorexia, nausea and vomiting, fever, hypoglycaemia, hypotension and dehydration.
Drug-induced adrenocortical insufficiency may be minimised by 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 that period, hormone therapy should be reinstituted.
A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may occur following abrupt discontinuance of glucocorticoids. 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 low corticosteroid levels.
Because glucocorticoids can produce or aggravate Cushing’s syndrome, glucocorticoids should be avoided in patients with Cushing’s disease.
Corticosteroids should be used with caution in patients with hypothyroidism as there is potential for an enhanced effect of corticosteroids in these patients.
Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.
Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes and predisposes those on long term corticosteroid therapy to diabetes mellitus. Therefore, corticosteroids should be used with caution in patients with diabetes mellitus or a family history of diabetes mellitus.
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Therefore, particular care is required when considering the use of corticosteroids in patients with existing or previous history of severe affective disorders.
Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Psychological effects have been reported upon withdrawal of corticosteroids; the frequency is unknown. Patients/caregivers should be encouraged to seek medical attention if psychological symptoms develop in the patient, especially 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 tapering/withdrawal of systemic steroids.
Corticosteroids should be used with caution in patients with seizure disorders.
Corticosteroids should be used with caution in patients with myasthenia gravis (see section 4.4, Musculoskeletal Effects).
There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible risk of corneal scarring, loss of vision and corneal perforation.
Prolonged use of corticosteroids may produce posterior 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. Establishment of secondary fungal and viral infections of the eye may also be enhanced in patients receiving glucocorticoids.
Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.
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, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects if high doses and/or prolonged courses are used. When using corticosteroids in these patients, attention should be paid to risk modification and additional cardiac monitoring should be considered.
Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.
Corticosteroids should be used with caution in patients with hypertension.
High doses of corticosteroids may produce acute pancreatitis.
There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy; however, 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 NSAIDs, the risk of developing gastrointestinal ulcers is increased.
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, or active or latent peptic ulcer, oesophagitis and gastritis.
Corticosteroids should be used with caution in patients with hepatic failure.
Hepatobiliary disorders have been reported which may be reversible after discontinuation of therapy. Therefore appropriate monitoring is required.
There is an enhanced effect of corticosteroids in patients with cirrhosis.
Corticosteroids should be used with caution in patients with myasthenia gravis who are receiving anticholinesterase therapy as corticosteroid use may decrease plasma anticholinesterase activity.
An acute myopathy has been reported with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g. myasthenia gravis) or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking drugs (e.g. pancuronium). This acute myopathy is generalised, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
Corticosteroids should be used with caution in patients with osteoporosis. Osteoporosis is a common but infrequently recognised adverse effect associated with a long-term use of large doses of glucocorticoid.
Corticosteroid should be used with caution in patients with Duchenne’s muscular dystrophy since transient rhabdomyolysis and myoglobinuria have been reported following strenuous activities.
Corticosteroids should be used with caution in patients with previous steroid myopathy.
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.
Corticosteroids should be used with caution in patients with renal insufficiency.
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
(see section 4.4, Endocrine Effects)
High doses of systemic corticosteroids should not be used for the treatment of traumatic brain injury.
Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids (see section 4.5, Other Interactions, NSAIDs).
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 are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.
Local injection of a steroid into a previously infected joint is to be avoided.
Corticosteroids should not be injected into unstable joints (see section 4.2).
Sterile technique is necessary to prevent infections or contamination.
The slower rate of absorption by intramuscular administration should be recognised.
Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Corticosteroids may cause growth retardation in infancy, childhood and adolescence. The effects may be irreversible, therefore, long-term daily divided doses of corticosteroids should be avoided in these patients.
In infants, children and adolescents, corticosteroid treatmentshould be restricted to the most serious indications. Use in children should be limited to the shortest possible time.
Increased intracranial pressure with papilloedema (pseudotumour cerebri) in children has been reported, usually after treatment withdrawal of methylprednisolone. Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.
High doses of corticosteroids may produce pancreatitis in children.
The use of corticosteroids, particularly long-term use, in the elderly should be planned bearing in mind the more serious consequences of the common side effects, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.
The pharmacokinetic interactions listed below are potentially clinically important.
Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is metabolised mainly by the CYP3A4 enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyses 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other medicines) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.
Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance, resulting in increased plasma concentration of methylprednisolone. Coadministration of CYP3A4 inhibitors may require titration of methylprednisolone dosage to reduce the risk of adverse effects and avoid steroid toxicity.
CYP3A4 inhibitors include:
Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentrations of methylprednisolone. Coadministration of these substances may require an increase in methylprednisolone dosage to achieve the desired result.
CYP3A4 inducers include:
In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration. Most CYP3A4 inhibitors are also CYP3A4 substrates.
Other interactions and effects that occur with methylprednisolone are described below.
Corticosteroids may increase blood glucose levels. Dose adjustments of antidiabetic therapy may be required with concurrent therapy.
Corticosteroids may influence the effect of anticholinergics.
Acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs (see section 4.4,MusculoskeletalEffects).
Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.
Steroids may reduce the effects of anticholinesterases in myasthenia gravis.
The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices (such as INR or prothrombin time) should be monitored to maintain the desired anticoagulant effects.
Aminogluethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
There is a risk of toxicity if hypokalaemia occurs due to corticosteroid treatment.
Excessive potassium loss maybe experienced with concurrent use of corticosteroids and potassium depleting diuretics (such as frusemide and thiazides) or carbonic anhydrase inhibitors (such as acetazolamide). Patients should be observed closely for development of hypokalaemia. There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B, xanthines, or beta2 agonists.
The effect of corticosteroids may be reduced for 3-4 days after taking mifepristone.
Concomitant administration may increase the risk of gastrointestinal bleeding and ulceration.
Methylprednisolone may increase the renal clearance of high-dose aspirin, which can lead to decreased salicylate serum levels. Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which could lead to an increased risk of salicylate toxicity.
Concomitant administration may inhibit the growth promoting effect of somatropin.
There is an increased risk of hypokalaemia with concurrent high doses of corticosteroids and sympathomimetics such as salbutamol, salmeterol, terbutaline or formoterol.
Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Some animal studies have shown that corticosteroids (such as methylprednisolone), have been shown to increase the incidence of foetal malformations of various kinds (cleft palate, ventricular septal defect, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation. However, corticosteroids do not appear to cause congenital anomalies when given to pregnant women. Since adequate human reproductive studies have not been done with methylprednisolone acetate, this medicinal product should be used during pregnancy only after a careful assessment of the benefit-risk ratio to the mother and fetus.
Corticosteroids readily cross the placenta. An increased incidence of low-birth weights in infants born of mothers receiving corticosteroids has been reported.In humans, the risk of low birth weight appears to be dose related and may be minimised by administering lower corticosteroid doses.
Infants born to mothers who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency, although neonatal adrenal insufficiency is rarely reported in infants exposed in utero to corticosteroids.
Cataracts have been observed in infants born to mothers treated with long-term corticosteroids during pregnancy.
There are no known effects of corticosteroids on labour and delivery.
Corticosteroids are excreted in breast milk.
Corticosteroids distributed into breast milk may suppress growth and interfere with endogenous glucocorticoid production in nursing infants. This medicinal product should be used during breast feeding only after a careful assessment of the benefit-risk ratio to the mother and infant.
Animal studies on the effects of methylprednisolone did not show an adverse impact on fertility in male and female rats treated with methylprednisolone aceponate at subcutaneous doses up to 0.1 mg/kg/day, although there was an increase in the number of non-viable fetuses. Other corticosteroids have been shown to impair fertility and reduce embryonic viability in studies in mice and rats
The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.
Administration by other than indicated routes has been associated with reports of serious medical events including: arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, headache, functional gastrointestinal disorder/bladder dysfunction, seizures, visual impairment including blindness, ocular and periocular inflammation, and residue or slough at injection site.
The adverse effects are listed in the table below by system organ class and frequency.
Not known: Opportunistic infection, infectiona, peritonitisf, oesophageal candidiasis, injection site infectionb.
Not known: Leucocytosis.
Not known: Drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction.
Not known: Cushingoid, hypopituitarism, steroid withdrawal syndrome.
Not known: Metabolic acidosis, sodium retention, fluid retention, alkalosis hypokalaemic, dyslipidaemia, glucose tolerance impairedc, increased insulin requirement (or oral hypoglycaemic agents in diabetics), lipomatosis, increased appetite (which may result in weight increased).
Not known: Affective disorder (including depressed mood, euphoric mood, affect lability, drug dependence, suicidal ideation), psychotic disorder (including mania, delusion, hallucination and schizophrenia), psychotic behaviour, mental disorder, personality change, confusional state, anxiety, mood swings, abnormal behaviour, insomnia, irritability.
Not known: Epidural lipomatosis, intracranial pressure increased (with papilloedema [benign intracranial hypertension]), seizure, amnesia, cognitive disorder, dizziness, headache.
Not known: Chorioretinopathy, blindnessd, cataract, glaucoma, exophthalmos, corneal thinning, scleral thinning, exacerbation of ophthalmic viral or fungal disease, vision blurred (see also section 4.4).
Not known: Vertigo.
Not known: Cardiac failure congestive (in susceptible patients).
Not known: Thrombosis, hypertension, hypotension.
Not known: Pulmonary embolism, hiccups.
Not known: Peptic ulcer (with possible peptic ulcer perforation and peptic ulcer haemorrhage), intestinal perforation, gastric haemorrhage, pancreatitis, oesophagitis ulcerative, oesophagitis, abdominal distension, abdominal pain, diarrhoea, dyspepsia, nausea.
Not known: Angioedema, hirsutism, petechiae, ecchymosis, subcutaneous atrophy, skin atrophy, erythema, hyperhidrosis, skin striae, rash, pruritus, urticaria, telangiectasia, acne, skin hyperpigmentation, skin hypopigmentation.
Not known: Muscular weakness, myalgia, myopathy, muscle atrophy, osteoporosis, osteonecrosis, pathological fracture, neuropathic arthropathy, arthralgia, growth retardation.
Not known: Menstruation irregular, amenorrhoea.
Not known: Abscess sterile, impaired healing, oedema peripheral, fatigue, malaise, injection site reaction, post-injection flaree.
Not known: Intraocular pressure increased, carbohydrate tolerance decreased, blood potassium decreased, calcium balance negative, urine calcium increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, suppression of reactions to skin testsg.
Not known: Spinal compression fracture, tendon rupture.
a Including increased susceptibility to and severity of infections, masking of infections and latent infections (e.g. tuberculosis) becoming active.
b Following non-sterile administration.
c Manifestations of latent diabetes mellitus.
d Rare instances of blindness associated with intralesional therapy around the face and head.
e Following intra-articular use.
f Peritonitis may be the primary presenting sign or symptom of a gastrointestinal disorder such as perforation, obstruction or pancreatitis (see section 4.4).
g Not a MedDRA preferred term.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
Because of possible physical incompatibilities, Depo-Medrol sterile aqueous suspension (methylprednisolone acetate) should not be diluted or mixed with other solutions.
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