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Indications:

Methylprednisolone is mainly used as an anti-inflammatory or immunosuppressive agent for the treatment of certain diseases including hematologic, allergic, inflammatory, cancerous and autoimmune causes.

Administration, dosage:

Administration

Methylprednisolone is taken orally, after achieving a satisfactory dose, the dose must be gradually reduced to the lowest dosage that will maintain an adequate clinical response.

For long–term methylprednisolon therapy, ADT (Alternate Day Therapy) regimen should be considered.

After long-term therapy, treatment usually needs to be stopped gradually.

Dosage

Adults: Initial dose: 2 – 60 mg daily, depending on the disease being treated, usually administered in 4 divided doses.

Allergic disease (contact dermatitis): Initial recommended dose: 24 mg on the first day, followed by a taper by 4 mg per day, taken for 6 days.

Asthma: Adults and adolescents who have at least 2 severe asthma attacks yearly; 40 to 60 mg daily taken as single dose or two divided doses. Maintenance dose of inhaled corticosteroids or long-acting beta2 agonists may be added. A short (3-10 days) oral corticosteroid therapy may be continued until positive expiratory pressure (PEP) breathing of patients achieves 80% of their maximum expiratory pressure and until symptoms disappear. Once asthma is well controlled, corticosteroid dose should be reduced.

Some special attention on the handling of the medicine before and after use:

There are no special requirements for handling this medicine after use.

 

Contraindications:

A known hypersensitivity to methylprednisolone or any of excipients.

Severe infections, except septic shock and tuberculous meningitis.

Skin lesions caused by viruses, fungi or tuberculosis.

Receiving live virus vaccines.

Warnings and precautions for use:

Immunosuppressant effects/Increased susceptibility to infections: Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may occur during their use. These infections may be mild, but may also be serious, sometimes fatal.

Effects on immune system: Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken before administration, especially when the patient has a history of allergy to any drug.

Endocrine effects: In patients on corticosteroid therapy subjected to unusual (stress), increased dosage of rapidly acting corticosteroids is indicated before, during, and after the stressful situation.

Long term use of corticosteroids at pharmacological doses may lead to hypothalamus-pituitary-adrenal (HPA) axis suppression (secondary adrenal insufficiency). The level and duration of secondary adrenal insufficiency vary between patients and depend on the dose, frequency, duration of use and duration of glucocorticoid therapy. This effect can be minimized by alternate day therapy (see Dosage and Administration – Alternate day therapy).

In addition, adrenal insufficiency also leads to death if glucocorticoids are suddenly stopped.

Drug-induced secondary adrenocortical insufficiency may be minimized 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. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

A steroid “withdrawal syndrome” unrelated to adrenocortical insufficiency may also occur following sudden 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 due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels.

Glucocorticoids may cause or aggravate Cushing’s syndrome, therefore glucocorticoids should be avoided in patients with Cushing’s disease.

The effects of corticosteroids increase in patients with hypothyroidism.

Metabolism and nutrition disorders: Corticosteroids, including methylprednisolone, may increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.

Psychiatric effects: Psychosis may appear with corticosteroid use, ranging from euphoria, insomnia, mood change, temperament change, and severe depression to actual psychotic manifestations. Unstable emotions or psychotic tendency may also be more severe due to corticosteroids.

Potentially severe psychiatric adverse reactions may occur with systemic steroids (see Undesirable effects – Psychiatric disorders). Typical symptoms occur within a few days or weeks of starting treatment. Most reactions disappear with dose reduction or discontinuation, although specific treatment is required. Psychiatric effects, without known frequency, have been reported with corticosteroid withdrawal.

Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms appear, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids.

Nervous system effects: Particular care is required when using systemic corticosteroids in patients with seizure disorders and severe myasthenia gravis (see myopathy statement in Musculoskeletal effects section) and frequent patient monitoring is necessary.

There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.

Ocular effects: Systemic corticosteroids should be taken with caution in patients with glaucoma (or a family history of glaucoma) and ocular Herpes simplex as there is a fear of corneal perforation.

Prolonged use of corticosteroids may cause 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. Secondary ocular infections due to fungi or viruses may also be enhanced in patients receiving glucocorticoids.

Corticosteroid therapy has been associated with chorioretinopathy, which may lead to retinal detachment.

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 used with caution in such patients and attention should be paid to risk decrease and additional cardiac monitoring if needed. Low dose and alternate day therapy may reduce the incidence of complications in corticosteroid therapy.

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, thromboembolic disorders.

Gastrointestinal effects:

Caution should be exercised when using corticosteroids in ulcerative colitis, abscess or other pyogenic infections; diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer.

Risk of developing peptic ulcer is increased when methylprednisolone is administered concurrently with nonsteroidal anti-inflammatory drugs (NSAIDs).

Hepatobiliary effects: High doses of corticosteroids may cause acute pancreatitis.

Caution should be exercised when systemic corticosteroid therapy is used in patients with hepatic insufficiency or cirrhosis and frequent patient monitoring is necessary.

Musculoskeletal effects: 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 generalized, 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.

Particular care is required when considering the use of systemic corticosteroids in patients with osteoporosis (post-menopausal females are particularly at risk) and frequent patient monitoring is necessary.

Renal and urinary effect: Caution should be exercised when considering the use of corticosteroids in patients with renal insufficiency.

Injury, poisoning and surgery complications: High doses of systemic corticosteroids should not be used to treat traumatic brain injury.

Other warnings: 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 alternate day therapy should be used.

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 nonsteroidal anti-inflammatory drugs should be used cautiously in conjunction with corticosteroids.

Pheochromocytoma, 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.

Effect of vaccination can be affected by steroid use.

Paediatric administration: Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.

Glucocorticoids cause growth retardation in children. Treatment should be limited to the minimum dosage for the shortest possible time. This side effect may be avoided or minimized with alternate day glucocorticoids therapy  (see Dosage and Administration – Alternate day therapy).

Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.

High doses of corticosteroids may induce pancreatitis in children.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

Ingredient warning: This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy and lactation:

Pregnancy

Long-term use of systemic methylprednisolone in mothers may lead to slight weight loss in infants. In general, this medicine should be used with caution during pregnancy, and only if the expected benefit to the mother is greater than any possible risk to the developing baby.

Lactation

Methylprednisolone is excreted into breast milk; therefore, caution should be used when administering this drug to nursing mothers.

Effects on ability to drive and use machines:

Caution should be excercised when prescribing methylprednisolone to patients driving motor vehicles and operating machinery because this drug may cause dizziness, nervous excitability, psychosis, headache, mood changes, delirium, and hallucinations.

Interactions, incompatibilities of medicine:

Interaction with other medicinal products and other forms of interaction:

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 or inhibition of the CYP3A4 enzyme.

The interactions and effects on methylprednisolone when given in combination with other drugs are presented in the following table:

Drug class or type – Drug or substance	Interaction	Effect
Antibiotic, antitubercular – Rifampin – Rifampicin – Rifabutin	CYP3A4 inducer	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.
Anticonvulsants – Phenobarbital – Phenytoin – Primidone
Anticonvulsant – Carbamazepine	CYP3A4 inducer (and substrate)	CYP3A4 inducers – see box above 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.
Macrolide antibacterial – Troleandomycin	CYP3A4 inhibitor	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 adjusted to avoid steroid toxicity.
– Grapefruit juice
Calcium antagonist – MIBEFRADIL
Histamine H2 receptor antagonist – Cimetidine
Antibacterial – Isoniazid		In addition, there is a potential effect of methylprednisolone to increase the acetylation rate and clearance of isoniazid.
Antiemetic – APREPITANT – FOSAPREPITANT	CYP3A4 Inhibitor (and Substrate)	CYP3A4 inhibitors – see box above 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. (1) Mutual inhibition of metabolism occurs with concurrent use of ciclosporine 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) Protease inhibitors, such as indinavir and ritonavir, may increase plasma concentrations of corticosteroids. (3) Corticosteroids may increase the metabolism of HIV-protease inhibitors resulting in reduced plasma concentrations.
Antifungal – Itraconazole – Ketoconazole
Calcium channel blocker – Diltiazem
Contraceptives (oral) – Ethinylestradiol/ norethindrone
Immunosuppressant – Ciclosporine (1)
Macrolide antibacterial – Clarithromycin – Erythromycin
Antivirals – HIV-protease inhibitors (2) (3)
Immunosuppressant – Cyclophosphamide – Tacrolimus	CYP3A4 substrate	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.
NSAIDs (nonsteroidal anti-inflammatory drugs) (4) – ASPIRIN (acetylsalicylic acid) high-dose (5)	Non-CYP3A4-mediated effects	(4) There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs. (5) 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.
Anticholinergics (6) – Neuromuscular blockers (7)		(6) An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics (such as neuromuscular blocking drugs). (See section Conditions where caution should be taken: Musculoskeletal system, for additional information.) (7) 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.
Anticoagulants (oral)		The efficacy of coumarin anticoagulants may be changed by concurrent corticosteroid therapy. Therefore, close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
Potassium-depleting agents		When corticosteroids are administered concomitantly with potassium-depleting agents (i.e. thiazide and loop diuretics), 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, xanthenes, or beta2 agonists.
Aromatase inhibitors -AMINOGLUTETHIMIDE		Aminoglutethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.

Incompatibilities:

Because there are no studies about the incompatibility of the medicine, it should not be mixed with other medicines.

Undesirable effects:

Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”.

Undesirable effects most commonly occur when taking high doses of methylprednisolone for long time.

Methylprednisolone inhibits the synthesis of prostaglandins and counteracts the effect of prostaglandins on the gastrointestinal tract, including inhibition of gastric acid secretion and gastric mucosal protection. A lot of ADRs are related to this effect of glucocorticoid.

Common

Central nervous system: Insomnia, nervousness.

Gastrointestinal: Increased appetite, dyspepsia.

Dermatologic: Hirsutism.

Endocrine and metabolic: Diabetes.

Neuromuscular & skeletal: Arthralgia.

Ocular: Cataracts, glaucoma.

Respiratory: Epistaxis.

Uncommon

Central nervous system: Dizziness, convulsions, psychosis, pseudo-tumor cerebri, headache, mood changes, delirium, hallucinations, euphoria.

Cardiovascular: Edema, hypertension.

Dermatologic: Skin atrophy, acne, bruise, hyperpigmentation.

Endocrine and metabolic: Cushing’s syndrome, pituitary-adrenal axis suppression, growth retardation, glucose intolerance, hypokalemia, alkalosis, amenorrhea, sodium and water retention, hyperglycaemia.

Gastrointestinal: Peptic ulcer, nausea, vomiting, abdominal distension, esophagitis ulcerative, pancreatitis.

Neuromuscular & skeletal: Muscular weakness, osteoporosis, bone fractures.

Others: Hypersensitivity reactions.

Guidelines for ADR management

In acute indications, the lowest effective dose of methylprednisolone should be used for shortest possible time to achieve clinical effect.

After long-term treatment with methylprednisolone, if hypothalamic pituitary adrenal axis suppression may occur, it is urgent to taper the dose of methylprednisolone gradually, instead of stopping abruptly.

Apply the treatment regime to avoid the continuous impact of pharmacologically active doses. ADRs caused by single daily dose is less than those caused by subdivided doses, and alternate-day therapy is an effective measure to reduce adrenal suppression and other ADRs. In the alternate-day therapy, a single dose is taken every two days, in the morning.

Data of osteoporosis, hematopoiesis, glucose tolerance, glucose tolerance, effects on eyes and blood pressure should be closely monitored and evaluated periodically.

Duodenal and gastric ulcers can be prevented by using H2-histamine receptor antagonists when high doses of systemic methylprednisolone are taken.

Calcium supplements to prevent osteoporosis should be given to all patients treated with long–term courses of methylprednisolone.

The patient who is likely immunosuppressed should be warned about the possibility of more susceptibility to infection.

Patients who are going to undergo surgery may have to take supplemental methylprednisolone as normal response to stress has been reduced by hypothalamic-pituitary-adrenal axis suppression.

Overdose and management:

Overdose: Symptoms of overdose include the manifestations of Cushing’s syndrome (body as a whole), muscle weakness (body as a whole), and osteoporosis (body as a whole). All symptoms only occur under long–term glucocorticoid treatment.

When very high doses are used for long term, the overactive adrenal glands and adrenal gland suppression can occur.

Management: In these cases a right decision should be made whether to suspend or to discontinue glucocorticoid treatment.

Pharmacodynamic properties:       

Pharmacotherapeutic group: Synthetic glucocorticoid

ATC code: H02AB04

Methylprednisolone, a synthetic glucocorticoid, is 6-alpha-methyl derivative of prednisolone used as anti-inflammatory or immunosuppressive agent.

Due to the methylation of prednisolone, methylprednisolone has only minimal mineralocorticoid effects (little effect on salt metabolism) and is not suitable to be used alone to treat adrenocortical insufficiency. If methylprednisolone is used in this case, an adjuvant   mineralocorticoid should be administered.

Methylprednisolone has anti-inflammatory, immunosuppressive and anti-proliferative effects. The anti-inflammatory effect is due to reduction of production, release and activity of anti-inflammatory mediators caused by methylprednisolone (such as histamine, prostaglandin, leucotrienes etc.); therefore, it reduces the initial manifestations of inflammatory process.

Methylprednisolone inhibits leukocytes to bind to injured vessel walls and migrate to injured sites, reduces the permeability of these sites, therefore, small number of leukemia cells reach injured sites. This effect causes the reduction of extravasation, swelling, edema, pain.

With immunosuppressive property methylprednisolone reduces the response to both slow and prompt reactions (type III and type IV). This is due to the inhibition of toxic effect of the antigen – antibody complexes that cause cutaneous allergic vasculitis.  Corticosteroids reduce allergic contact dermatitis by inhibiting the action of lymphokines, target cells, and macrophages. In addition, corticosteroids also prevent T-lymphocytes and sensitive macrophages from migration to target cells. The anti-proliferative effect reduces proliferative tissue which is the characteristics of psoriasis.

Pharmacokinetic properties:

Absorption: Bioavailability is approximately 80%. The maximum effect is reached 1-2 hours after administration. Duration of action lasts 30–36 hours after oral administration.

Metabolism: Methylprednisolone is metabolized in the liver, similar to the metabolism of hydrocortisone.

Excretion: The metabolites are excreted in urine. Half-life is approximately 3 hours, reduced in obese people.

Storage conditions, shelf – life, quality specification of the medicine:

Storage conditions: Protect from humidity and light, below 300C.

Shelf – life: 36 months from the manufacture date.

Quality specification: In house specification.

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