Glucocorticoids should only be considered as a purely symptomatic treatment, unless in case of some endocrine disorders, where they are used as substitution treatment.

 

Anti-inflammatory treatment

·       Rheumatic disorders

As adjunctive therapy for short‑term administration (to tide the patient over an acute episode or exacerbation) in:

-        Post-traumatic osteoarthritis

-        Synovitis of osteoarthritis

-        Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low‑dose maintenance therapy)

-        Acute and subacute bursitis

-        Epicondylitis

-        Acute nonspecific tenosynovitis

-        Acute gouty arthritis

-        Psoriatic arthritis

-        Ankylosing spondylitis

·       Collagen diseases (immune complex diseases)

During an exacerbation or as maintenance therapy in selected cases of:

-        Systemic lupus erythematosus (and lupus nephritis)

-        Acute rheumatic carditis

-        Systemic dermatomyositis (polymyositis)

-        Polyarteritis nodosa

-        Goodpasture's syndrome

·        Dermatologic diseases

-        Pemphigus

-        Severe erythema multiforme (Stevens‑Johnson syndrome)

-        Exfoliative dermatitis

-        Bullous dermatitis herpetiformis

-        Severe seborrheic dermatitis

-        Severe psoriasis

-        Mycosis fungoides

-        Urticaria

·       Allergic states

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in:

-        Bronchial asthma

-        Contact dermatitis

-        Atopic dermatitis

-        Serum sickness

-        Drug hypersensitivity reactions

-        Urticarial transfusion reactions

-        Acute noninfectious laryngeal edema (epinephrine is the drug of first choice)

·       Ophthalmic diseases

Severe acute and chronic allergic and inflammatory processes involving the eye, such as:

-        Herpes zoster ophthalmicus

-        Iritis, iridocyclitis

-        Chorioretinitis

-        Diffuse posterior uveitis and choroiditis

-        Optic neuritis

-        Sympathetic ophthalmia

·       Gastrointestinal diseases

To tide the patient over a critical period of the disease in:

-        Ulcerative colitis (systemic therapy)

-        Regional enteritis (systemic therapy)

·        Respiratory diseases

-        Pulmonary sarcoidosis

-        Berylliosis

-        Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy

-        Loeffler's syndrome not manageable by other means

-        Aspiration pneumonitis

·       Edematous states
To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

Immunosuppressive treatment

·       Organ transplantation

 

Treatment of hematological and oncological disorders

·        Hematologic disorders

-        Acquired (autoimmune) hemolytic anemia

-        Idiopathic thrombocytopenica purpura in adults (intravenous only; intramuscular administration is contraindicated)

-        Secondary thrombocytopenia in adults

-        Erythroblastopenia (R.B.C. anemia)

-        Congenital (erythroid) hypoplastic anemia

·       Oncological diseases

For palliative management of:

-     Leukemias and lymphomas in adults

-     Acute leukemia of childhood

 

Others

·        Nervous system

-        Cerebral edema from tumor ‑ primary or metastatic and/or associated with surgical or radiation therapy

-        Acute exacerbations of multiple sclerosis

-        Acute spinal cord injury. The treatment should begin within eight hours of injury.

·        Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy

·        Trichinosis with neurological or myocardial involvement

·       Prevention of nausea and vomiting associated with cancer chemotherapy

 

Endocrine disorders

·        Primary or secondary adrenocortical insufficiency

·       Acute adrenocortical insufficiency

For these indications, the drugs of choice are hydrocortisone or cortisone. Synthetic analogues can be used in certain circumstances if they are combined with mineralocorticoids.

·        Treatment of shock conditions: shock resulting from adrenocortical insufficiency or shock that does not respond to conventional treatment, in the case of confirmed or suspected adrenocortical insufficiency (in general, hydrocortisone is the preparation of choice. If mineralocorticoid effects are undesired, preference can be given to methylprednisolone).

·        Prior to surgical procedures and in the case of severe disease or injury, in patients with known adrenocortical insufficiency or doubtful adrenal reserves.

·        Congenital adrenal hyperplasia

·        Nonsuppurative thyroiditis

·        Hypercalcaemia associated with cancer

Posology

See table below for recommended dosages.

 

Recommended dosages of methylprednisolone sodium succinate

 

Indication	Posology
As adjunctive therapy in life-threatening conditions	The recommended dose is 30 mg per kg, given intravenously over a period of at least 30 minutes. This dose may be repeated in the hospital every 4 to 6 hours for 48 hours depending on the clinical necessity (see section 4.4).
"PULSE‑THERAPY" in case of very serious exacerbation and/or unresponsive to standard therapy, as nonsteroidal inflammatory means, gold salts and penicillamine.	Suggested schedules: -     Rheumatoid arthritis: -     1 g/day intravenous for 1, 2, 3 or 4 days or -     1 g /month intravenous for 6 months. As high doses of corticosteroids can cause an arythmogenic action, this therapy should be restricted to hospitals, which dispose of an electrocardiograph and defibrillator. The regimen should be administered over at least 30 minutes and may be repeated if no improvement has been reported within one week after therapy or if the patient's condition dictates.
Prevention of nausea and vomiting associated with cancer chemotherapy	Suggested schedules: -     Mild to moderately emetogenic chemotherapy: Administer 250 mg intravenous over at least 5 minutes one hour before chemotherapy, at the initiation of chemotherapy and at the time of discharge. A chlorinated phenothiazine may also be used with the first dose of for increased effect. -     Severely emetogenic chemotherapy: Administer 250 mg intravenous over at least 5 minutes with appropriate doses of metoclopramide or a butyrophenone one hour before chemotherapy, then 250 mg intravenous at the initiation of therapy and at time of discharge.
Acute spinal cord injury	The treatment should begin within eight hours of injury. For patients initiated on treatment within 3 hours of injury : Start with an I.V. bolus dose of 30 mg methylprednisolone per kilogram of body weight over a 15 minute period under continuous medical supervision.   After the bolus injection comes a 45 minute pause, followed by a continuous infusion of 5,4 mg/kg per hour for 23 hours.   For patients initiated on treatment within 3 to 8 hours of injury : Start with an I.V. bolus dose of 30 mg methylprednisolone per kilogram of body weight over a 15 minute period under continuous medical supervision. After the bolus injection comes a 45 minute pause, followed by a continuous infusion of 5,4 mg/kg per hour for 47 hours.   For the infusion pump, one should preferably choose another intravenous site than for the bolus injection.   The administration rate of the bolus injection may only be used for this indication, under ECG-monitoring and with an available defibrillator. The administration of a high dose of methylprednisolone in bolus intravenously (doses of more than 500 mg over a period of less than 10 minutes) may cause arrhythmias, circulatory collapse and cardiac arrest.
In other indications	initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short‑term management of severe, acute conditions as bronchial asthma, serum sickness, urticarial transfusion reactions and acute exacerbations of multiple sclerosis. The initial dose, up to and including 250 mg, should be given intravenously over a period of at least 5 minutes and doses exceeding 250 mg, should be given over at least 30 minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition. Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

 

Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine laboratory studies, such as urinalysis, two‑hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X‑ray should be made at regular intervals during prolonged therapy. Upper GI X‑rays are desirable in patients with an ulcer history or significant dyspepsia.
Medical surveillance is also needed in case of interruption of chronic treatment.
To administer by intravenous (or intramuscular) injection, prepare solution as directed.

 

Paediatric population

Dosage for children should be based upon the principles of dosing in adults (see above) and should be adjusted based on severity of the condition and clinical response. Treatment should be limited to the minimum dosage necessary to achieve a favourable response and for the shortest period of time. If after long term therapy the medicinal product is to be discontinued, it is advisable to reduce the dose gradually rather than to stop abruptly.

If possible, treatment should be administered as a single dose on alternate days (see section 4.4).

 

NOTE: Certain methylprednisolone sodium succinate formulations contain benzyl alcohol (see section 4.4 “Paediatric population”).

 

Elderly

Treatment of elderly patients, particularly if long-term, should be planned bearing in mind the potential for more serious consequences of corticosteroids in old age, particularly osteoporosis, diabetes, hypertension, susceptibility to infection and thinning of skin (see section 4.4). 

 

Method of administration 

The solution of sodium succinate of methylprednisolone may be administered by intravenous or intramuscular injection or by intravenous infusion. Intravenous injection is preferable for commencing treatment in cases of emergency.

• Hypersensitivity to methylprednisolone or to any of the excipients listed in section 6.1. • Solu-Medrol Act-O-Vial 40 mg is contraindicated in patients with a known or suspected allergy to cow’s milk (see section 4.4). • Patients with systemic fungal infections. • Intrathecal route of administration. • Epidural route of administration.

Immunosuppressant effects/Increased susceptibility to infections

Glucocorticosteroids may increase susceptibility to infections, may mask some signs of infection and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections due to bacteria, viruses, fungi, protozoa or worms, in any part of the body, may be associated with the use of corticosteroids either alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity or neutrophil action. These infections can be moderate, severe and occasionally fatal. As the corticosteroid dose increases, more infections occur.

 

Patients treated with immunosuppressive medicinal products are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults treated with corticosteroids.

 

Administration of live or live attenuated vaccines is not recommended in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines and biogenetic vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the therapeutic reaction to these vaccines may be diminished or even ineffective. Patients on non-immunosuppressive doses of corticosteroids may undergo any required immunisation procedures.

 

Patients under corticosteroid therapy cannot be vaccinated against smallpox. The other vaccinations should be avoided in patients under corticosteroid therapy, especially when used in high doses, due to the potential neurological complications and altered immune response.

 

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis, where appropriate anti-tuberculosis regimen is initiated simultaneously.

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 in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

 

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. One systematic review of short-course, high-dose corticosteroids did not support their use. However, meta-analyses, and one review of the literature suggest that longer courses (5–11 days) of low-dose corticosteroids may reduce mortality, especially in patients with vasopressor-dependent septic shock.

 

Immune system effects

Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions 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 medicinal product.

 

Endocrine effects

In patients treated with corticosteroids subjected to unusual stress, an increased dose of rapidly acting corticosteroids may be required before, during and after the stressful situation.

 

Pharmacological doses of glucocorticoids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) axis suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency is variable among patients and depends on the dose, frequency, time of administration, and duration of glucocorticoid therapy. This effect may be minimised by alternate-day therapy.

 

In addition, acute adrenal insufficiency with a fatal outcome may occur if glucocorticoids are withdrawn abruptly.

 

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.

 

Steroid “withdrawal syndrome,” seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuation 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, they should be avoided in patients with this syndrome.

 

The effect of corticosteroids is enhanced in patients with hypothyroidism.

 

Metabolism and nutrition

Corticosteroids, including methylprednisolone, may increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus. These patients should be treated while under close medical supervision, and for the shortest period possible.

 

Psychiatric effects

Psychiatric disorders ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations may appear during treatment with corticosteroids. Existing emotional instability or psychotic tendencies may also be aggravated by corticosteroids.

 

Potentially severe adverse psychiatric reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal of the treatment, 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.

 

Nervous system effects

Corticosteroids should be used with caution in patients with seizure disorders.

 

Corticosteroids should be used with caution in patients with myasthenia gravis (see remarks on myopathy in the section “Musculoskeletal effects” below).

 

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute episodes in multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary for a significant effect to appear.

 

Severe medical events have been reported in association with the intrathecal/epidural routes of administration (see section 4.8).

 

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

 

Ocular effects

Corticosteroids should be used with caution in patients with ocular herpes simplex or herpes zoster associated with ocular symptoms due to the risk of 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. Glucocorticoids may also promote the appearance of secondary fungal or viral infections of the eye.

 

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.

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

 

Cardiac effects

Side effects of glucocorticoids on the cardiovascular system, such as dyslipidaemia and hypertension, may predispose treated patients with other existing cardiovascular risk factors to additional cardiovascular effects, in case of prolonged high-dose treatment. Accordingly, corticosteroids should be used with caution in such patients. Attention should be paid to changes in risk, and additional cardiac monitoring should be provided if required. Low dose and alternate-day treatment may reduce the incidence of complications.

 

There are reports of cardiac arrhythmias, and/or circulatory collapse, and/or cardiac arrest following the rapid administration of high intravenous doses of methylprednisolone sodium succinate (more than 0.5 g administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of high doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion.

 

Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.

 

Vascular effects

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.

 

Steroids should be used with caution in patients with hypertension, as the risk of increased arterial hypertension is further elevated. These patients should be treated while under close medical supervision, and for the shortest period possible.

 

Gastrointestinal effects

High doses of corticosteroids may produce acute pancreatitis.

 

There is no universal consensus regarding the involvement of corticosteroids per se in the appearance peptic ulcers encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer, and 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 risk of impending perforation, abscess or other pyogenic infections, diverticulitis, fresh intestinal anastomoses, or active or latent peptic ulcer.

 

Hepatobiliary effects

Hepatobiliary effects: drug induced liver injury including acute hepatitis or liver enzyme increase can result from cyclical pulsed intravenous 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.

 

High doses of corticosteroids may cause acute pancreatitis.

The effect of glucocorticoids is more significant in cases of cirrhosis.

 

Musculoskeletal effects

Acute myopathy has been reported with the use of high corticosteroid doses, usually in patients with disorders of neuromuscular transmission (for example, myasthenia gravis), or in patients receiving concurrent treatment with anticholinergics, such as neuromuscular blockers (for example, pancuronium). This acute myopathy is generalized, can affect eye muscles and respiratory muscles and can result in quadriparesis. Increased creatine kinase levels can occur. After discontinuation of the corticosteroid treatment it may take weeks to years before clinical improvement or recovery occurs.

 

Osteoporosis is a common but rarely recognised side effect associated with the long-term, high-dose use of glucocorticoids.

 

Renal and urinary disorders

Corticosteroids should be used with caution in patients with renal impairment.

 

Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.

 

Investigations

Average and high 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 at high doses. Dietary salt restriction and potassium supplements may be necessary. All corticosteroids increase calcium excretion.

 

Treatment with corticosteroids must be taken into consideration when interpreting certain biological tests (particularly skin tests, thyroid hormone levels).

 

Injury, poisoning and procedural complications

Systemic corticosteroids are not indicated for and therefore should not be used to treat traumatic brain injury. One multicentre study revealed an increased mortality in the 2 weeks and 6 months following trauma in patients administered methylprednisolone sodium succinate compared to placebo (relative risk 1.18). No causal association with methylprednisolone sodium succinate treatment has been established.

 

Injection in the deltoid muscle should be avoided due to the high risk of subcutaneous atrophy.

 

Other

Since complications of treatment with glucocorticoids are dependent on the dose and the duration of treatment, the dose, frequency and duration of administration (daily or alternate-day), a decision must be made in each individual case, taking into consideration the risks and benefits.

 

The lowest possible dose of corticosteroids should be used to control the condition and, when a dose reduction is possible, the reduction should be gradual.

 

The duration of treatment should in general be kept as short as possible. Medical surveillance is recommended during chronic treatment (see section 4.2). The gradual discontinuation of chronic treatment should also take place under medical surveillance (gradual discontinuation, evaluation of adrenocortical function). The most important symptoms of adrenocortical insufficiency are asthenia, orthostatic hypotension and depression.

 

Acetylsalicylic acid and nonsteroidal anti-inflammatory agents should be used with caution in combination with corticosteroids.

 

An attack of pheochromocytoma, which can be fatal, was reported after administration of systemic corticosteroids. Corticosteroids may only be administered to patients with suspected or identified pheochromocytoma after an appropriate assessment of benefits/risks.

 

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 (see section 4.5).

 

In post marketing experience tumor lysis syndrome (TLS) has been reported in patients with malignancies, including hematological malignancies and solid tumors, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumors that have a high proliferative rate, high tumor burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.

 

Solu-Medrol 40 mg and 125 mg solution for injection contain less than 1 mmol sodium (23 mg) per vial or Act-O-Vial, that is to say essentially 'sodium-free'.

 

Solu-Medrol 500 mg Powder and solvent for solution for injection contains 58.39 mg sodium per vial.

Solu-Medrol 1000 mg Powder and solvent for solution for injection contains 116.78 mg sodium per vial.

 

This should be taken into account for the WHO recommended maximum daily intake of 2 g sodium for an adult.

 

Paediatric population

Some of these presentations contain benzyl alcohol. Reconstituted solutions of Solu-Medrol contain 9 mg benzyl alcohol per ml. Benzyl alcohol may cause allergic reactions. Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known. Benzyl alcohol must not be given to a newborn baby (up to 4 weeks old), unless recommended by the doctor. Due to increased risk due to accumulation in young children, benzyl alcohol must not be used for more than a week in young children (less than 3 years old), unless advised by the doctor or pharmacist. High volumes should be used with caution and only if necessary, especially in pregnant or breast-feeding women or in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

 

Allergic reactions to cow’s milk proteins should be considered in patients receiving Solu-Medrol Act-O-Vial 40 mg for the treatment of acute allergic conditions in whom symptoms worsen or who are presenting new allergic symptoms (see section 4.3). Administration of Solu-Medrol Act-O-Vial 40 mg should be stopped, and the patient’s condition should be treated accordingly.

 

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully monitored. Growth may be suppressed in children receiving long-term, daily, divided-dose glucocorticoid therapy and this regimen should be restricted to the most urgent indications. Alternate-day glucocorticoid therapy usually avoids or minimises this side effect.

 

Infants and children treated with corticosteroids in the long term are at particular risk of increased intracranial pressure.

 

High doses of corticosteroids may cause pancreatitis in children.

 

Cases of transient myocardial hypertrophy have been reported in premature neonates receiving corticosteroid therapy for lung diseases.

 

Children should be treated while under close medical supervision, and for the shortest period possible.

Methylprednisolone is a cytochrome P450 (CYP) substrate and is mainly metabolised 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 (along with other medicinal products) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

 

CYP3A4 INHIBITORS – Medicinal products 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.

 

CYP3A4 INDUCERS – Medicinal products that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medicinal products that are substrates for CYP3A4. Co-administration may require an dose increase of methylprednisolone to achieve the desired result.

CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, and corresponding dose adjustments may therefore be required. It is possible that adverse events associated with the use of either medicinal product alone may be more likely to occur with co-administration.

EFFECTS NOT MEDIATED BY CYP3A4 – Other interactions and effects that occur with methylprednisolone are described in the table below.

The table provides a list and descriptions of the most common and/or clinically important drug interactions or effects with methylprednisolone.

Important drug or substance interactions/effects with methylprednisolone

Medicinal product class or type      - MEDICINAL PRODUCT or SUBSTANCE	Interaction/Effect
Antibacterial       - ISONIAZID	CYP3A4 INHIBITOR. In addition, there is a potential effect of methylprednisolone increasing the acetylation rate and clearance of isoniazid.
Antibiotic, Antitubercular       - RIFAMPIN	CYP3A4 INDUCER
Anticoagulants (oral)	The effect of methylprednisolone on oral anticoagulants is variable.  There have been reports of enhanced as well as diminished effects of anticoagulants when administered concomitantly with corticosteroids. Coagulation indices should therefore be monitored to maintain the desired anticoagulant effects.
Anticonvulsants       - CARBAMAZEPINE	CYP3A4 INDUCER (and SUBSTRATE)
Anticonvulsants       - PHENOBARBITAL       - PHENYTOIN	CYP3A4 INDUCERS
Anticholinergics        - NEUROMUSCULAR          BLOCKING AGENTS	Corticosteroids may influence the effect of anticholinergics. 1) Acute myopathy has been reported with concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking agents (for more information, see section 4.4 “Musculoskeletal effects”); 2) Antagonism of the neuromuscular blocking effects induced by pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may occur with all competitive neuromuscular blocking agents.
Anticholinesterases	Steroids may reduce the effects of anticholinesterases in myasthenia gravis.
Antidiabetics	Because corticosteroids may increase blood glucose concentrations, dose adjustments of antidiabetic agents may be required.
Antiemetics          - APREPITANT       - FOSAPREPITANT	CYP3A4 INHIBITORS (and SUBSTRATES)
Antifungal       - ITRACONAZOLE       - KETOCONAZOLE	CYP3A4 INHIBITORS (and SUBSTRATES)
Antivirals       - HIV-PROTEASE         INHIBITORS	CYP3A4 INHIBITORS (and SUBSTRATES) 1) Protease inhibitors, such as indinavir and ritonavir, may increase plasma concentrations of corticosteroids. 2) Corticosteroids may induce the metabolism of HIV-protease inhibitors and thus reduce their plasma concentrations.
Pharmacokinetic enhancers                          - COBICISTAT	CYP3A4 INHIBITORS Pharmacokinetic enhancers inhibit CYP3A4 activity leading to a decreased hepatic clearance and increased plasma concentration of corticosteroids. A dose adjustment of the corticosteroid may be required (see section 4.4).
Aromatase inhibitors       - AMINOGLUTETHIMIDE	Aminoglutethimide-induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
Calcium channel blockers       - DILTIAZEM	CYP3A4 INHIBITOR (and SUBSTRATE)
Contraceptives (oral)       - ETHINYLESTRADIOL/         NORETHISTERONE	CYP3A4 INHIBITOR (and SUBSTRATE)
- GRAPEFRUIT JUICE	CYP3A4 INHIBITOR
Immunosuppressants      - CICLOSPORIN	CYP3A4 INHIBITOR (and SUBSTRATE) 1) Mutual inhibition of metabolism occurs with concurrent use of ciclosporin and methylprednisolone, which may increase the plasma concentrations of either or both substances. It is possible that side effects associated with the use of either alone may be more likely to occur upon coadministration. 2) Convulsions have been reported with concomitant use of methylprednisolone and ciclosporin.
Immunosuppressants      - CYCLOPHOSPHAMIDE      - TACROLIMUS	CYP3A4 SUBSTRATES
Macrolide antibacterials      - CLARITHROMYCIN      - ERYTHROMYCIN	CYP3A4 INHIBITORS (and SUBSTRATES)
Macrolide antibacterials      - TROLEANDOMYCIN	CYP3A4 INHIBITOR
NSAIDs (nonsteroidal anti-inflammatory drugs)       - high-dose acetylsalicylic          acid	1) There may be an increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are administered with NSAIDs. 2) Methylprednisolone may increase the clearance of high-dose acetylsalicylic acid, which can lead to decreased salicylate serum levels. Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which may result in an increased risk of salicylate toxicity. 3) Acetylsalicylic acid should be used with caution in combination with corticosteroids in hypoprothrombinaemia.
Potassium depleting agents	When corticosteroids are administered concomitantly with potassium depleting agents (i.e., diuretics), patients should be closely monitored for potential development of hypokalaemia. The combination of glucocorticoids with thiazide-diuretics increases the risk of glucose intolerance.   There is also an increased risk of hypokalaemia where corticosteroids are used concomitantly with amphotericin B, xanthenes, or beta2 mimetics.

 

Incompatibilities

To avoid compatibility and stability problems, it is recommended to administer methylprednisolone sodium succinate separately from other compounds administered via the IV route. Medicinal products physically incompatible in solution with methylprednisolone sodium succinate include, but are not limited to: allopurinol sodium, doxapram hydrochloride, tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate, propofol (see section 6.2).

 

DESIRED INTERACTIONS

In treatment of neoplastic disease such as leukaemia and lymphoma, methylprednisolone is usually used in combination with alkylating agents, antimetabolites and vinca alkaloids. 

Pregnancy

Some animal studies have shown that corticosteroids when administered during pregnancy at high doses, may cause foetal malformations (see section 5.3).

Administration of corticosteroids in pregnant women however does not appear to induce congenital anomalies. In the absence of adequate studies of the effects of methylprednisolone sodium succinate on human reproduction, this medicinal product should only be used during pregnancy following careful evaluation of the ratio of benefits to risks for the mother and the foetus. If a chronic treatment with corticosteroids has to be stopped during pregnancy (as with other chronic treatments), this should occur gradually (see section 4.2). In some cases (e.g. substitution treatment of adrenocortical insufficiency) however, it can be necessary to continue treatment or even to increase dosage.

Some corticosteroids readily cross the placenta. One retrospective study revealed an increased incidence of low-birth weight in infants born to mothers treated with corticosteroids. In humans, the risk of low birth weight seems dose-dependent and can be reduced by administering lower doses of corticosteroids. Though neonatal adrenocortical insufficiency is rare in infants who were exposed in utero to corticosteroids, infants who were exposed to substantial doses of corticosteroids should be carefully observed and evaluated for signs of adrenocortical insufficiency.

 

Cases of cataracts have been observed in infants born to mothers having received prolonged treatment with corticosteroids during pregnancy.

 

There are no known effects of corticosteroids on labour and delivery.

 

Benzyl alcohol can cross the placenta (see section 4.4). This warning does not apply to Solu-Medrol S.A.B. (without benzyl alcohol).

 

Lactation

Corticosteroids are excreted in breast milk.

 

Corticosteroids in breast milk may suppress growth and interfere with endogenous glucocorticoid production in nursing infants. This medicinal product should only be used while breastfeeding following careful evaluation of the ratio of benefits to risks for the mother and the infant.

 

Fertility

Corticosteroids have been shown to impair fertility in animal studies (see section 5.3).

Solu-Medrol has a minor influence on the ability to drive and use machines. Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or use machines.

Safety profile summary

The following undesirable side effects are typical of methylprednisolone sodium succinate.  Hypersensitivity reactions may occur at the start of treatment (see section 4.4). Serious infections, including opportunistic infections, may also occur during treatment with corticosteroids. Other side effects include: convulsions, pathological fractures and vertebral settlement fractures, gastric ulcers with perforation or haemorrhage, torn tendons, psychiatric disorders or manifestations, Cushing's syndrome, steroid withdrawal syndrome, hypertension, myopathy, glaucoma, subcapsular cataract, decreased glucose tolerance, rash, fluid retention, abdominal pain, nausea, headaches and dizziness. 

 

The following side effects have been reported with the following contraindicated routes of administration: intrathecal/epidural: arachnoiditis, functional gastrointestinal disorder/bladder dysfunction, headache, meningitis, paraparisis/paraplegia, convulsions, sensory disturbances. The frequency of these side effects is not known.

 

Table of side effects
System organ class MedDRA	Frequency not known (cannot be estimated from the available data)
Infections and infestations	Infection; opportunistic infection, peritonitis*.
Blood and lymphatic system disorders	Leukocytosis.
Immune system disorders	Drug hypersensitivity (including anaphylactic and anaphylactoid reactions).
Endocrine disorders	Cushing syndrome, hypothalamic pituitary adrenal axis suppression, steroid withdrawal syndrome.
Metabolism and nutrition disorders	Metabolic acidosis, lipomatosis, sodium retention, fluid retention, hypokalaemic alkalosis, dyslipidaemia, impaired glucose tolerance, increased insulin requirements (or oral hypoglycaemic agents in diabetics), increased appetite (which may result in weight gain).
Psychiatric disorders	Affective disorders (including depressed mood, euphoria, affect lability, pharmacological dependence, suicidal ideation), psychotic disorders (including mania, delusion, hallucination, and schizophrenia), mental disorders, personality change, confusional state, anxiety, mood swings, abnormal behaviour, insomnia, irritability.
Nervous system disorders	Epidural lipomatosis, increased intracranial pressure (with papilloedema [benign intracranial hypertension]), convulsions, amnesia, cognitive disorder, dizziness, headache.
Eye disorders	Chorioretinopathy, cataract, glaucoma (with potential optic nerve lesions), exophthalmos, vision blurred (see section 4.4).
Ear and labyrinth disorders	Vertigo.
Cardiac disorders	Congestive heart failure (in predisposed patients), arrhythmia, myocardial rupture following myocardial infarction. Cases of cardiac arrhythmia and/or circulatory collapse and/or cardiac arrest have been reported upon rapid intravenous administration of high doses of methylprednisolone sodium succinate (more than 0.5 g in less than 10 minutes). Bradycardia has been observed during or after administration of high doses of methylprednisolone sodium succinate, which may also occur regardless of the rate or duration of infusion. Tachycardia has been reported after administration of high doses of glucocorticoids.
Vascular disorders	Thrombotic events, hypertension, hypotension, flushing.
Respiratory, thoracic and mediastinal disorders	Pulmonary embolism, hiccups.
Gastrointestinal disorders	Peptic ulcer (with risk of perforation and haemorrhage), intestinal perforation, gastric haemorrhage, pancreatitis, ulcerative oesophagitis, oesophagitis, abdominal distention, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting.
Hepatobiliary disorders	Hepatitis†, elevated liver enzymes (for example AST, ALT).
Skin and subcutaneous tissue disorders	Angioedema, hirsutism, petechiae, ecchymosis, skin atrophy, erythema, hyperhidrosis, skin striae, rash, pruritus, urticaria, acne, skin hypopigmentation. Local atrophy may be observed at the site of injection in case of repeated subcutaneous injections.
Musculoskeletal and connective tissue disorders	Muscular weakness, myalgia, myopathy, muscular atrophy, osteoporosis, osteonecrosis, pathological fracture, neuropathic arthropathy, arthralgia, growth retardation.
Reproductive system and breast disorders	Irregular menstruation.
General disorders and administration site conditions	Peripheral oedema, impaired healing, fatigue, malaise, injection site reactions.
Investigations	Increased urine calcium, decreased blood potassium, increased intraocular pressure, decreased carbohydrate tolerance, increased blood urea, increased alanine aminotransferase; increased aspartate aminotransferase; increased blood alkaline phosphatase; suppression of reactions to skin tests.
Injury, poisoning and procedural complications	Spinal compression fracture, tendon rupture.

* Peritonitis may be the main sign or symptom of the onset of a gastrointestinal disorder, such as perforation, obstruction or pancreatitis (see section 4.4).

^† Hepatitis has been reported with intravenous administration (see section 4.4).

 

Paediatric population

The frequency, type and severity of undesirable effects in children are expected to be the same as in adults.

 

Growth may be suppressed in children receiving long-term glucocorticoid therapy (see section 4.4).

 

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to their local requirements.  

 

To Report side effects

 

·       Saudi Arabia

 

National Pharmacovigilance Centre (NPC) ·       Call center: 19999 ·       E-mail: npc.drug@sfda.gov.sa ·       Website: https://ade.sfda.gov.sa/

 

·       Other GCC States

 

-   Please contact the relevant competent authority.

Symptoms

There is no clinical syndrome of acute overdose with corticosteroids. Reports of acute toxicity and/or death following overdose of corticosteroids are rare. In the event of overdose, no specific antidote is available; supportive and symptomatic treatment should be initiated. Chronic overdose induces typical Cushing-type symptoms.

 

Treatment

There is no specific antidote in case of overdose; symptomatic support should be started.

Methylprednisolone is dialysable.

Pharmacotherapeutic group: glucocorticosteroid, ATC H02AB04

 

Glucocorticoids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the numerous effects of glucocorticoids after systemic use. Glucocorticoids not only have an important influence on inflammatory and immune processes, but also affect the carbohydrate, protein and fat metabolism. They also act on the cardiovascular system, the skeletal muscles and the central nervous system.

-     Effect on the inflammatory and immune process:
The anti‑inflammatory, immunosuppressive and anti‑allergic properties of glucocorticoids are responsible for most of the therapeutic applications. These properties lead to the following results:

-     reduction of the immunoactive cells near the inflammation focus;

-     reduced vasodilation;

-     stabilization of the lysosomal membranes;

-     inhibition of phagocytosis;

-     reduced production of prostaglandines and related substances.

A dose of 4 mg methylprednisolone has the same glucocorticosteroid (anti‑inflammatory) effect as 20 mg hydrocortisone. Methylprednisolone has only a minimal mineralocorticoid effect (200 mg methylprednisolone are equivalent to 1 mg desoxycorticosterone).

-    Effect on carbohydrate and protein metabolism:
Glucocorticoids have a protein catabolic action. The liberated amino acids are converted into glucose and glycogen in the liver by means of the gluconeogenesis process. Glucose absorption in peripheral tissues decreases, which can lead to hyperglycemia and glucosuremia, especially in patients who are prone to diabetes.

-    Effect on fat metabolism:
Glucocorticoids have a lipolytic action. This lipolytic activity mainly affects the limbs. They also have a lipogenetic effect which is most evident on chest, neck and head. All this leads to a redistribution of the fat deposits.

 

Maximum pharmacologic activity of corticosteroids lags behind peak blood levels, suggesting that most effects of the drugs result from modification of enzyme activity rather than from direct actions by the drugs.

Methylprednisolone pharmacokinetics is linear, independent of route of administration.

 

Absorption

In vivo, cholinesterases rapidly hydrolyze methylprednisolone sodium succinate to free methylprednisolone.
In man, methylprednisolone forms a weak dissociable bond with albumin and transcortin. Approximately 40 to 90% of the drug is bound.
Intravenous infusions with 30 mg/kg, administered over 20 minutes or 1 g administered over 30 to 60 minutes lead after approximately 15 minutes to peak methylprednisolone plasma levels of nearly 20 µg/ml. About 25 minutes after an intravenous bolus injection of 40 mg peak methylprednisolone plasma values of 42‑47 µg/100 ml are measured. Intramuscular injections of 40 mg give peak methylprednisolone plasma levels of 34 µg/100 ml after some 120 minutes. Intramuscular injections give lower peak values than intravenous injections. With intramuscular injections plasma values persist for a longer period, with the result that both administration patterns lead to equivalent quantities of methylprednisolone. The clinical importance of these small differences is probably minimal when we consider the mechanism of action of glucocorticoids.
A clinical response is usually observed 4 to 6 hours after administration. In the treatment of asthma, the first beneficial results can already be perceived after 1 or 2 hours. The plasma half‑life of methylprednisolone sodium succinate is 2.3 to 4 hours and appears to bear no relation to the administration pattern.
Methylprednisolone is a glucocorticoid with a medium‑term activity. It has a biological half‑life of 12 to 36 hours. The intracellular activity of glucocorticoids results in a clear difference between plasma half‑life and pharmacological half‑life. Pharmacological activity persists after measurable plasma levels have disappeared. The duration of anti‑inflammatory activity of glucocorticoids approximately equals the duration of hypothalamic‑pituitary‑adrenal (HPA) axis suppression.
Following intravenous administration of C14 labelled methylprednisolone, 75% of the total radioactivity was recovered in the urine in 96 hours, 9% was recovered in human faeces after 5 days and 20% in the bile.

 

Distribution

Methylprednisolone is widely distributed in the tissues, crosses the blood-brain barrier, and is excreted in breast milk. Its apparent volume of distribution is approximately 1.4 l/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.

 

Biotransformation

Methylprednisolone is metabolised in the liver in a manner qualitatively similar to cortisol. The metabolites are mainly excreted in the urine as glucuronides, sulfates and unconjugated compounds.

 

In humans, methylprednisolone is metabolised in the liver to inactive metabolites; principally 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone.

Metabolism in the liver is primarily via CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5)

 

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for p-glycoprotein, a protein in the ATP-binding cassette (ABC) transport protein family, which influences tissue distribution and interactions with other medicinal products.

 

Elimination

The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 ml/min/kg.

 

Specific populations

 

Sex

The clearance of methylprednisolone was higher in healthy women than in healthy men after intravenous administration of a single dose: 0.45 versus 0.29 l/h/kg. There were nonetheless no differences in pharmacodynamic measures.

 

Elderly

Methylprednisolone clearance in healthy elderly men (69–82 years) was lower than in younger men (24–37 years) after intravenous administration of a single dose: 0.24 versus 0.36 l/h/kg.

 

Paediatric population

The clearance of methylprednisolone is mildly related to age. Younger subjects tend to metabolise methylprednisolone more rapidly. In a study of intravenous administration of a single dose in 14 patients with nephrotic syndrome, younger subjects (<13 years) showed greater clearance than the older group (>13 years): 0.53 versus 0.38 l/h/kg.

 

Renal impairment

In a single-dose intravenous study in 6 male subjects with chronic renal impairment, the pharmacokinetics of methylprednisolone remained unchanged compared to healthy controls, with an average clearance of 0.28 l/h/kg. In addition, no differences in pharmacodynamic measures were observed in these subjects with chronic renal failure.

 

Hepatic impairment

In a single-dose intravenous study in 6 male subjects with chronic liver disease, the pharmacokinetics of methylprednisolone were similar to those in healthy controls, with an average clearance of 0.29 l/h/kg. 

 

Based on conventional studies of safety pharmacology, and repeated- dose toxicity no unexpected hazards were identified. The toxicities seen in the repeated-dose studies are those expected to occur with continued exposure to exogenous corticosteroids.

 

Carcinogenic potential

Methylprednisolone has not been formally evaluated in carcinogenicity studies on rodents. Other glucocorticoids have been tested for carcinogenicity on mice and rats with variable results. However, published data indicates that several similar glucocorticoids, in particular, budesonide, prednisolone and triamcinolone acetonide, may increase the incidence of adenomas and hepatocellular carcinomas after oral administration in the drinking water of male rats. These carcinogenic effects occurred at doses lower than the usual clinical doses expressed in mg/m2.

 

Mutagenic potential

There was no evidence of a potential for genetic or chromosome mutations in limited studies in bacterial and mammalian cells.

 

Reproductive toxicity

Corticosteroids administered to male rats have been shown to reduce fertility. In rats, corticosterone induced a reduction in seminal plugs, the number of implantations and viable foetuses.

 

Corticosteroids are teratogenic in many animal species at administration of doses equivalent to the ones used in humans. In animal reproduction studies, glucocorticoids such as methylprednisolone have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-foetal demise (such as an increase in reabsorption) and intra-uterine growth retardation.

Solution for injection: Act-O-Vial system:

·        Solu-Medrol 40 mg Solution for injection: Sucrose, monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, Sodium hydroxide, and water for injection

·        Solu-Medrol 125 mg Solution for injection: monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, Sodium hydroxide, and water for injection

 

Powder and solvent for solution for injection:

·        Solu-Medrol 500 mg – 1000 mg - Powder and solvent for solution for injection:

-     Powder: monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous.

-     Solvent: benzyl alcohol, water for injection.

Intravenous compatibility and stability of methylprednisolone sodium succinate solutions and with other drugs in intravenous admixtures are dependent on admixture pH, concentration, time, temperature and the ability of methylprednisolone to solubilize itself. Thus, to avoid compatibility and stability problems, whenever possible it is recommended that solutions of methylprednisolone sodium succinate be administered separate from other drugs and as either intravenous push, through and intravenous medication chamber or as an intravenous "piggy‑back" solution (see section 4.5 for more information).

• Do not use Solu Medrol after the expiry date which is stated on the carton / Vial label after EXP:. • Solu-Medrol 40 mg and 125 mg Powder for solution: 24 months. • Solu-Medrol 500 mg Powder and solvent for solution for injection: 24 months. • Solu-Medrol 1000 mg Powder and solvent for solution for injection: 30 months. The expiry date refers to the last day of that month. Solu-Medrol 40 mg Powder for solution After reconstitution with solvent: Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 48 hours at 2°C to 8°C. It should be used immediately if stored below 25°C. After reconstitution with solvent and further dilution for infusion: Chemical and physical in-use stability of the reconstituted and further diluted solution has been demonstrated for 24 hours at 2°C to 8°C. It should be used within 3 hours if stored at 20°C to 25°C. Other presentations After reconstitution with solvent: Chemical and physical in-use stability of the reconstituted product has been demonstrated for a period of 12 hours and not above 25°C. After reconstitution with solvent and further dilution for infusion: The resulting solutions should be used within 3 hours of reconstitution if stored at 20°C to 25°C or within 24 hours of reconstitution if stored at 2°C to 8°C. From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Unreconstituted product:

·        Do not store above 30°C.

·        Do not freeze.

 

Solutions reconstituted with water for injection (Reconstituted Solution):

Store reconstituted solution below 25°C and use immediately or store reconstituted solution at 5°C ± 3°C and use within 48 hours.

 

Further dilution for infusion (admixture), also called as Perfusion:

Dilute and use resulting solution within 12 hours following reconstitution if stored below 25°C or within 48 hours of reconstitution if stored at 2°C to 8°C.

 

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

The product is packed in the following type of containers:

 

• Act-O-Vial or Vials: Type I glass vial
• Stoppers: butyl rubber.

 

Solu-Medrol 40 mg Solution for injection: 1 Act‑O‑Vials.

Solu-Medrol 125 mg Solution for injection: 1 Act‑O‑Vial.

Solu-Medrol 500 mg Powder and solvent for solution for injection: 1 vial + 1 vial.

Solu-Medrol 1000 mg Powder and solvent for solution for injection: 1 vial + 1 vial.

 

Bacteriostatic water for injection contains benzyl alcohol.

Keep out of the sight and reach of children.

 

DIRECTIONS FOR USE OF THE ACT-O-VIAL

1.    Press down on plastic activator to force diluent into the lower compartment.

2.    Gently agitate to effect solution.

3.    Remove plastic covering center of stopper.

4.    Sterilize top of stopper with a suitable germicide.

Note: steps 1-4 musts be completed before proceeding.

5.    Insert needle, preferably a 22G, vertically through center of stopper until tip is just visible. Turn the vial and draw up the required dose. If a thicker needle is used, it is important to avoid to turn the needle and to insert it perpendicularly to the center of rubber stopper.

 

DIRECTIONS FOR USE OF THE VIAL

Under aseptic conditions add the diluent to the vial with sterile powder. Do only use the special diluent.

To withdraw the dose from the vial, please refer to point 5 “Directions for use of the Act-O-Vial” regarding the size of the needle to be preferably used.

 

PREPARATION OF PERFUSION SOLUTIONS

First reconstitute the solution as directed. Therapy may be initiated by administering the methylprednisolone sodium succinate solution intravenously over a period of at least 5 minutes (e.g. doses up to and including 250 mg) to at least 30 minutes (e.g. doses exceeding 250 mg). Subsequent doses may be withdrawn and administered similarly. If desired, the medication may be administered in dilute solutions by admixing the reconstituted product with dextrose 5% in water, normal saline, dextrose 5% in 0,45% or 0,9% sodium chloride.  For in-use shelf life and storage conditions, see section 6.3.

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.