METHYLPREDNISOLONE VIATRIS

/ Dexcel

The first administration must be done in a hospital. 5 mg of prednisone is equivalent in terms of anti-inflammatory potency to 4 mg of methylprednisolone.
This proprietary medicinal product is not suitable for inhalation using a nebulizer. This drug is reserved for cases requiring high dose corticosteroid therapy.
Dosage: Acute symptoms of rheumatoid arthritis, extra-renal symptoms of certain systemic diseases, certain cases of systemic necrotizing vasculitis, initial treatment for certain cases of glomerulopathy: 500 mg to 1 g per day, Organ transplantation, graft rejection: 10 to 15 mg/kg/day, Graft versus host reaction: 10 to 20 mg/kg/day and up to 500 mg/m² every 6 hours for 48 hours. The powder is mixed with water for injections and the resulting solution should be administered intravenously:
Either directly by slow injection, minimum duration = 20 to 30 minutes. Or by infusion after dilution in isotonic sodium chloride or glucose solution for injection. Such high dose corticosteroid therapy is generally limited to 3 to 5 days.

Any condition in which IV corticosteroid treatment is required such as: Endocrine disorders, rheumatic disorders, collagen diseases, immune complex diseases, dermatologic diseases, allergic states, ophthalmic diseases, gastrointestinal diseases, respiratory diseases, hematologic disorders, management of neoplastic diseases, edematous states, nervous system disorders and organ transplantation.

* Patients who have systemic fungal infections unless specific anti-infective therapy is employed and in cerebral oedema in malaria.
* Hypersensitivity to methylprednisolone or to any of the excipients.
* For use by the intrathecal route of administration.
* Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Immunosuppressant Effects/Increased Susceptibility to Infections
Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.
Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids.
Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.
Exposure to measles should be avoided. Medical advice should be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immunoglobulin may be needed.
Parasitic infections, corticosteroids should be used with great care in patients with known or suspected parasitic infections such as Strongyloides (threadworm) infestation, which may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
Tuberculosis, The use of corticosteroids 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 anti-tuberculous regimen. If corticosteroids are indicated, 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.
This product should not be used in the treatment of septic syndrome or septic shock.
Immune System Effects
Allergic reactions may occur. Rarely skin reactions and anaphylactic/anaphylactoid reactions have been reported.
Endocrine Effects
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 minimized by use of alternate-day therapy.
In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly.
In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt.
Drug-induced secondary adrenocortical insufficiency may therefore be minimized by gradual reduction of dosage. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of
6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.
Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant
HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:
* Repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
* Short course has been prescribed within one year of cessation of long-term therapy (months or years).
* Additional causes of adrenocortical insufficiency other than exogenous corticosteroid therapy.
* Doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.
* Repeated taking doses in the evening.
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 also 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.
There is an enhanced effect of corticosteroids on patients with hypothyroidism. Frequent patient monitoring is necessary in patients with hypothyroidism.
Metabolism and Nutrition
Frequent patient monitoring is necessary in patients with diabetes mellitus (or a family history of diabetes). Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.
Psychiatric Effects
Patients 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 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. Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.
Nervous System Effects
Corticosteroids should be used with caution in patients with seizure disorders. Frequent patient monitoring is necessary in patients with epilepsy.
Corticosteroids should be used with caution in patients with myasthenia gravis. Frequent patient monitoring is necessary in patients with myasthenia gravis.
Severe medical events have been reported in association with the intrathecal/epidural routes of administration.
There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.
Ocular Effects
A patient who 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. Central serous chorioretinopathy, may lead to retinal detachment.
Frequent patient monitoring is necessary in patients with glaucoma (or a family history of glaucoma) and in patients with ocular herpes simplex, for fear of corneal perforation.
Establishment of secondary fungal and viral infections of the eye may also be enhanced in patients receiving glucocorticoids.
Cardiac Effects
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 prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed. Low dose and alternate day therapy may reduce the incidence of complications in corticosteroid therapy.
There have been a few reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest associated with the rapid intravenous administration of large doses of methylprednisolone (greater than 500 mg administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone, and may be unrelated to the speed and duration of infusion.
Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.
Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss.
Frequent patient monitoring is necessary in patients with congestive heart failure or recent myocardial infarction (myocardial rupture has been reported).
Vascular Effects
Steroids should be used with caution in patients with hypertension. Frequent patient monitoring is necessary.
Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result, corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.
Gastrointestinal Effects
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.
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary:
Ulcerative colitis, Perforation, Abscess or other pyogenic infections Diverticulitis, Fresh intestinal anastomoses, Peptic ulceration.
Hepatobiliary Effects
Drug induced liver injury including acute hepatitis or liver enzyme increase can result from cyclical pulsed IV methylprednisolone (usually at initial dose ≥ 1 g/day). Rare cases of hepatotoxicity have been reported. The time to onset can be several weeks or longer. In the majority of case reports resolution of the adverse events has been observed after treatment was discontinued. Therefore, appropriate monitoring is required.
Musculoskeletal Effects
Particular care is required when considering the use of systemic corticosteroids in patients with myasthenia gravis or osteoporosis (post-menopausal females are particularly at risk) and frequent patient monitoring is necessary.
Renal and urinary disorders
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled. Particular care is required when considering the use of systemic corticosteroids in patients with renal insufficiency and frequent patient monitoring is necessary.
Investigations
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.
Injury, poisoning and procedural complications
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury, a multicenter study revealed an increased mortality at 2 weeks and 6 months after injury in patients administered methylprednisolone compared to placebo. A causal association with methylprednisolone treatment has not been established.
Other
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 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 side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
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.
Aspirin and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.
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.
In post marketing experience 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 of TLS, such as patients with tumours that have a high proliferative rate, high tumour burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.
Severe medical events have been reported in association with the intrathecal/epidural routes of administration. There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.
Paediatric population
Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Growth may be suppressed in children receiving long-term, daily, divided- dose glucocorticoid therapy and use of such regimen should be restricted to the most urgent indications. Alternate-day glucocorticoid therapy usually avoids or minimizes this side effect. Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure. High doses of corticosteroids may produce pancreatitis in children.
Hypertrophic cardiomyopathy may develop after administration of methylprednisolone to prematurely born infants, therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure should be performed.
See prescribing information for full details

The following adverse reactions have been reported with the following routes of administration: Intrathecal/Epidural: Arachnoiditis, functional gastrointestinal disorder/bladder dysfunction, headache, meningitis, paraparesis/paraplegia, seizure and sensory disturbances. Under normal circumstances methylprednisolone therapy would be considered as short-term. However, the possibility of side-effects attributable to corticosteroid therapy should be recognised, particularly when high-dose therapy is being used.
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Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A4 enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 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 drugs) have been shown to alter glucocorticoid metabolism by induction (up-regulation) or inhibition of the CYP3A4 enzyme.
A list and descriptions of the most common and/or clinically important drug interactions or effects with methylprednisolone are provided below.
CYP3A4 INHIBITORS – Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.
Macrolide Antibacterial (TROLEANDOMYCIN), Antibacterial (ISONIAZID, GRAPEFRUIT JUICE) – An increase in the plasma concentration of methylprednisolone may occur. The dose of methylprednisolone may need to be titrated to avoid steroid toxicity
In addition, there is a potential effect of methylprednisolone to increase the acetylation rate and clearance of isoniazid.
CYP3A4 INDUCERS – Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Co-administration may require an increase in methylprednisolone dosage to achieve the desired result. Antibiotic, Antitubercular (RIFAMPIN), Anticonvulsants (PHENOBARBITAL, PHENYTOIN) – A decrease in the plasma concentration of methylprednisolone may occur. Co-administration may require an increase in methylprednisolone dosage to achieve the desired result.
CYP3A4 SUBSTRATES – 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 co-administration. Immunosuppressant (CYCLOPHOSPHAMIDE, TACROLIMUS) – The hepatic clearance of methylprednisolone may be inhibited or induced, resulting in an increase or decrease in the plasma concentration of methylprednisolone. A corresponding dosage adjustment may be required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with administration.
CYP3A4 INHIBITORS (and SUBSTRATES) – Antiemetic (APREPITANT, OSAPREPITANT), Antifungal (ITRACONAZOLE, KETOCONAZOLE), Antivirals (HIV-PROTEASE INHIBITORS), Pharmacokinetic enhancers (COBICISTAT), Calcium Channel Blocker (DILTIAZEM), Contraceptives (oral –ETHINYLESTRADIOL /NORETHISTERONE), Immunosuppressant (CICLOSPORIN), Macrolide Antibacterial (CLARITHROMYCIN, ERYTHROMYCIN) – The hepatic clearance of methylprednisolone may be inhibited or induced, resulting in an increase or decrease in the plasma concentration of methylprednisolone. A corresponding dosage adjustment may be required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with administration:
1. Protease inhibitors, such as indinavir and ritonavir, may increase plasma concentrations of corticosteroids
2. Corticosteroids may induce the metabolism of HIV protease inhibitors resulting in reduced plasma concentrations.
Ciclosporin
1. Mutual inhibition of metabolism occurs with concurrent use of ciclosprin and methylprednisolone, which may increase the plasma concentrations of either or both drugs. Therefore, it is possible that adverse events associated with the use of either drug alone may be more likely to occur upon co-administration.
2. Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin.
CYP3A4 INDUCER (and SUBSTRATE) – Anticonvulsants (CARBAMAZEPINE) – The hepatic clearance of methylprednisolone may be inhibited or induced, resulting in an increase or decrease in the plasma concentration of methylprednisolone. A corresponding dosage adjustment may be required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with administration.
NON-CYP3A4-MEDIATED EFFECTS – Other interactions and effects that occur with methylprednisolone are described below.
Anticoagulants (oral) – 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 should be monitored to maintain the desired anticoagulant effects.
Anticholinergics (NEUROMUSCULAR BLOCKERS) – Corticosteroids may influence the effect of anticholinergics.
1. An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs.
2. 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.
Anticholinesterases – Steroids may reduce the effects of anticholinesterases in myasthenia gravis.
Anti-diabetics – Because corticosteroids may increase blood glucose concentrations, dosage adjustments of anti-diabetic agents may be required.
Aromatase inhibitors (AMINOGLUTETHIMIDE) – Aminoglutethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
NSAIDs (non-steroidal anti-inflammatory drugs) – high-dose ASPIRIN (acetylsalicylic acid)
1. There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs.
2. Methylprednisolone may increase the 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.
Potassium depleting agents – When corticosteroids are administered concomitantly with potassium depleting agents (e.g. diuretics) patients should be observed closely for development of hypokalaemia. Corticosteroids antagonize the diuretic effect of diuretics.
There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B, xanthines, or beta2 agonists.
Corticosteroids antagonize the hypotensive effect of all antihypertensives.
There is an increased risk of hypokalaemia when corticosteroids are given with cardiac glycosides.
The effects of corticosteroids may be reduced for 3-4 days after mifepristone.
Incompatibilities- To avoid compatibility and stability problems, it is recommended that methylprednisolone be administered separately from other compounds that are administered via the IV route of administration. Drugs that are physically incompatible in solution with methylprednisolone include allopurinol sodium, doxapram hydrochloride, tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate and propofol.
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Pregnancy: The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta. Since adequate human reproductive studies have not been done with methylprednisolone, this medicinal product should be used during pregnancy only after a careful assessment of the benefit-risk ratio to the mother and fetus. In humans, the risk of low birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses. Cataracts have been observed in infants born to mothers undergoing long-term treatment with corticosteroids during pregnancy.
Lactation: Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. This medicinal product should be used during breast feeding only after a careful assessment of the benefit-risk ratio to the mother and infant.
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There is no clinical syndrome of acute overdosage with corticosteroids. Reports of acute toxicity and/or death following overdosage of corticosteroids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic. Methylprednisolone is dialysable. Following chronic overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further stressful episode.