SOLU MEDROL 500 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
METHYLPREDNISOLONE AS SODIUM SUCCINATE
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
H02AB04
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJ/INF
Composition:
METHYLPREDNISOLONE AS SODIUM SUCCINATE 62.5 MG/ML
Administration route:
I.M, I.V
Prescription type:
Required
Manufactured by:
PFIZER MANUFACTURING BELGIUM NV/SA
Therapeutic group:
METHYLPREDNISOLONE
Therapeutic area:
METHYLPREDNISOLONE
Therapeutic indications:
Solu Medrol is indicated to treat any condition in which IM or 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.
Authorization number:
114 09 22488 00
Authorization date:
2014-05-31

רזייפ יא ףא יפ מ"עב לארשי הקיטבצמרפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

רבמצד

2018

,ה/דבכנ ת/חקור ,ה/אפור

ולעב ןוכדע לע ךעידוהל וננוצרב

אפורל

לש

רישכתה :םי

Solu Medrol 40mg /ml

5mg

Solu Medrol 12

edrol 500mg

M

Solu

Solu Medrol 1000mg

:ליעפה ביכרמה

Solu-Medrol 40 mg: Methylprednisolone (as methylprednisolone sodium succinate) 40 mg.

Solu-Medrol 125 mg: Methylprednisolone (as methylprednisolone sodium succinate) 125 mg.

Solu-Medrol 500 mg: Methylprednisolone (as methylprednisolone sodium succinate) 500 mg.

Solu-Medrol 1000 mg: Methylprednisolone (as methylprednisolone sodium succinate) 1000 mg.

Indicated for:

Solu Medrol is indicated to treat any condition in which IM or 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.

:אפורל ןולעב םיירקיעה םינוכדעה ןלהל

4.4

Special warnings and precautions for use

………

Ocular Effects

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. 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.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts

(particularly in children), exophthalmos, or increased intraocular pressure, which may result in

glaucoma with possible damage to the optic nerves. Establishment of secondary fungal and viral

infections of the eye may also be enhanced in patients receiving glucocorticoids.

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

detachment.

……..

4.8

Undesirable effects

…….

Eye disorders

Rare

Vision blurred (see also section 4.4).

Not Known

Posterior subcapsular cataracts;

Exophthalmos; Glaucoma; Papilloedema with

possible damage to the optic nerve; Corneal or

scleral thinning; Exacerbation of ophthalmic

viral or fungal disease;

Chorioretinopathy.

…….

.הרמחה םיווהמ בוהצ עקרב םישגדומה םייונישה ינוכדעו עדימ תטמשה ,עדימ תפסות םיללוכה םיפסונ םייוניש ועצוב ,ןכ ומכ .הרמחה םיווהמ םניאש חסונ

ולעה םינ

כדועמה םי

חלשנ

ךרוצל תואירבה דרשמל מוסרפ

:תואירבה דרשמ רתאבש תופורתה רגאמב

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

ולע תלבקל ,ןיפוליחל םינ

אלמ םי

ספדומ םי

חל תונפל ןתינ יא ףא יפ רזייפ תרב מ"עב לארשי הקיטבצמרפ

רקנש

.ד.ת ,

12133

,חותיפ הילצרה

46725

רבב ,הכ

ידובע לטרוא

הנוממ תחקור

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

SOLU-MEDROL

40 mgSOLU-MEDROL

125 mg

SOLU-MEDROL

500 mg

SOLU-MEDROL

1000 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Solu-Medrol 40 mg:

Methylprednisolone (as methylprednisolone sodium succinate) 40 mg/ Act-o-vial.

Solu-Medrol 125 mg:

Methylprednisolone (as methylprednisolone sodium succinate) 125 mg/ Act-o-vial.

Solu-Medrol 500 mg:

Methylprednisolone (as methylprednisolone sodium succinate) 500 mg/ vial.

Solu-Medrol 1000 mg:

Methylprednisolone (as methylprednisolone sodium succinate) 1000 mg/ vial.

For the full list of excipients, see section 6.1.

Solu-Medrol 500 mg & 1000 mg contain Benzyl alcohol

(see Section 4.4 Special warnings and

precautions for use)

3.

PHARMACEUTICAL FORM

Powder for solution for injection or infusion

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Methylprednisolone sodium succinate is indicated in

the following conditions:

Endocrine Disorders

primary or secondary adrenocortical insufficiency (in conjunction with mineralocorticoids,

where applicable)

acute adrenocortical insufficiency (mineralocorticoid supplementation may be necessary)

shock secondary to adrenocortical insufficiency, or shock unresponsive to conventional

therapy when adrenal cortical insufficiency may be present (when mineralocorticoid activity

is undesirable)

preoperatively, or in the event of serious trauma or illness, in patients with known adrenal

insufficiency or when adrenocortical reserve is doubtful

congenital adrenal hyperplasia

nonsuppurative thyroiditis

hypercalcemia associated with cancer.

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Rheumatic Disorders

(as adjunctive therapy for short-term administration in the management

of an acute episode or exacerbation)

post-traumatic osteoarthritis

synovitis of osteoarthritis

rheumatoid arthritis, including juvenile rheumatoid arthritis

acute and subacute bursitis

epicondylitis

acute nonspecific tenosynovitis

acute gouty arthritis

psoriatic arthritis

ankylosing spondylitis.

Collagen Diseases and Immune Complex Diseases

(during an exacerbation or as maintenance

therapy in selected cases)

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

severe psoriasis

bullous dermatitis herpetiformis

severe seborrheic dermatitis

mycosis fungoides.

Allergic States

(to control severe or incapacitating allergic conditions intractable to adequate

trials of conventional treatment)

bronchial asthma

contact dermatitis

atopic dermatitis

serum sickness

seasonal or perennial allergic rhinitis

drug hypersensitivity reactions

urticarial transfusion reactions

acute non-infectious laryngeal oedema (epinephrine is the drug of first choice).

Ophthalmic Diseases

(severe acute and chronic allergic and inflammatory processes involving

the eye)

herpes zoster ophthalmicus

iritis, iridocyclitis

chorioretinitis

diffuse posterior uveitis and choroiditis

optic neuritis

sympathetic ophthalmia

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anterior segment inflammation

allergic conjunctivitis

allergic corneal marginal ulcers

keratitis.

Gastrointestinal Diseases

(to manage critical periods of the disease)

ulcerative colitis

regional enteritis.

Respiratory Diseases

symptomatic sarcoidosis

berylliosis

fulminating or disseminated tuberculosis (when used concurrently with appropriate

antituberculous chemotherapy)

Loeffler's syndrome not manageable by other means

aspiration pneumonitis

moderate to severe

Pneumocystis jiroveci

pneumonia in AIDS patients (as adjunctive

therapy when given within the first 72 hours of initial anti-pneumocystis treatment)

exacerbations of chronic obstructive pulmonary disease (COPD).

Hematologic Disorders

acquired (autoimmune) hemolytic anemia

idiopathic thrombocytopenic purpura in adults

secondary thrombocytopenia in adults

erythroblastopenia (RBC anemia)

congenital (erythroid) hypoplastic anemia.

Neoplastic Diseases

(palliative management)

leukemias and lymphomas in adults

acute leukemia of childhood

to improve quality of life in patients with terminal cancer.

Edematous States

To induce diuresis or remission of proteinuria in the nephrotic syndrome without uremia.

Nervous System

cerebral oedema from primary or metastatic tumors, or surgical or radiation therapy

acute exacerbations of multiple sclerosis

acute spinal cord injury. The treatment should begin within 8 hours of injury.

Other Indications

tuberculous meningitis with subarachnoid block or impending block (when used

concurrently with appropriate antituberculous chemotherapy)

trichinosis with neurologic or myocardial involvement

organ transplantation

prevention of nausea and vomiting associated with cancer chemotherapy.

4.2

Posology and method of administration

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Methylprednisolone sodium succinate may be administered by intravenous (IV) injection or

infusion, or by intramuscular (IM) injection. The preferred method for initial emergency use is

IV injection. See Table 1 for recommended dosages. Dosage may be reduced for infants and

children but should be selected based on the severity of the condition and the response of the

patient rather than on the age or weight of the patient. The paediatric dosage should not be less

than 0.5 mg/kg every 24 hours.

Table 1. Recommended dosages for methylprednisolone sodium succinate.

Indication

Dosage

Adjunctive therapy in

life-threatening

conditions

Administer

30 mg/kg

IV over a period of at least 30

minutes. Dose may be repeated every 4 to 6 hours for up to

48 hours.

Rheumatic disorders

unresponsive to

standard therapy (or

during exacerbation

episodes)

Administer either regimen as IV pulse dosing over at least

30 minutes. The regimen may be repeated if improvement

has not occurred within a week after therapy, or as the

patient's condition dictates.

1 g/day for 1 to 4 days,

or

1 g/month for 6 months.

Systemic lupus

erythematosus

unresponsive to

standard therapy (or

during exacerbation

episodes)

Administer 1 g/day for 3 days as IV pulse dosing over at

least 30 minutes. The regimen may be repeated if

improvement has not occurred within a week after therapy,

or as the patient's condition dictates.

Multiple sclerosis

unresponsive to

standard therapy (or

during exacerbation

episodes)

Administer 1 g/day for 3 or 5 days as IV pulse dosing over at

least 30 minutes. The regimen may be repeated if

improvement has not occurred within a week after therapy,

or as the patient's condition dictates.

Edematous states, such

as glomerulonephritis

or lupus nephritis,

unresponsive to

standard therapy (or

during exacerbation

episodes)

Administer either regimen as IV pulse dosing over at least

30 minutes. The regimen may be repeated if improvement

has not occurred within 1 week after therapy, or as the

patient's condition dictates.

30 mg/kg every other day for 4 days,

or

1 g/day for 3, 5 or 7 days.

Terminal cancer (to

improve quality of life)

Administer 125 mg /day IV for up to 8 weeks.

Prevention of nausea

and vomiting associated

with cancer

chemotherapy

For mild to moderately emetogenic chemotherapy:

Administer 250 mg IV over at least 5 minutes 1 hour before

start of chemotherapy. Repeat dose of methylprednisolone

at the initiation of chemotherapy and at the time of

discharge. A chlorinated phenothiazine may also be used

with the first dose of methylprednisolone for increased

effect.

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Table 1. Recommended dosages for methylprednisolone sodium succinate.

Indication

Dosage

For severely emetogenic chemotherapy:

Administer 250 mg IV over at least 5 minutes with

appropriate doses of metoclopramide or a butyrophenone 1

hour before start of chemotherapy. Repeat dose of

methylprednisolone at the initiation of chemotherapy and at

the time of discharge.

Acute spinal cord

injury

Treatment should begin within 8 hours of injury.

For patients initiated on treatment within 3 hours of injury:

Administer 30 mg/kg as an IV bolus over a 15-minute

period, followed by a 45-minute pause, and then a

continuous IV infusion of 5.4 mg/kg/h for 23 hours.

For patients initiated on treatment within 3 to 8 hours of

injury: Administer 30 mg/kg as an IV bolus over a 15-

minute period, followed by a 45-minute pause, and then a

continuous IV infusion of 5.4 mg/kg/h for 47 hours.

There should be a separate intravenous site for the infusion

pump.

Pneumocystis jiroveci

pneumonia in patients

with AIDS

Therapy should begin within 72 hours of initial anti-

pneumocystis treatment

One possible regimen is to administer 40 mg IV every 6 to

12 hours with gradual tapering over a maximum of 21 days

or until the end of pneumocystis therapy.

Due to the increased rate of reactivation of tuberculosis in

AIDS patients, consideration should be given to the

administration of antimycobacteria therapy if corticosteroids

are used in this high risk group. The patient should also be

observed for activation of other latent infections.

Exacerbation of chronic

obstructive pulmonary

disease (COPD)

Two dose regimens have been studied:

0.5 mg/kg IV every 6 hours for 72 hours,

or

125 mg IV every 6 hours for 72 hours, switch to an oral

corticosteroid and taper dose. Total treatment period should

be at least 2 weeks.

As adjunctive therapy

in other indications

Initial dose will vary from 10 to 500 mg IV, depending on

the clinical condition. Larger doses may be required for

short-term management of severe, acute conditions. Initial

doses up to 250 mg should be administered IV over a period

of at least 5 minutes, while larger doses should be

administered over at least 30 minutes. Subsequent doses

may be administered IV or IM at intervals dictated by the

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Table 1. Recommended dosages for methylprednisolone sodium succinate.

Indication

Dosage

patient's response and clinical condition.

To avoid compatibility and stability problems, it is recommended that methylprednisolone

sodium succinate be administered separately from other drugs whenever possible, as either

IV push, through an IV medication chamber, or as an IV "piggy-back" solution (see section

6.6).

NOTE: Some of the Methylprednisolone sodium succinate formulations contain benzyl alcohol

(see section 4.4 Special warnings and precautions for use, paediatric population).

Undesirable effects may be minimised by using the lowest effective dose for the minimum

period (see Other special warnings and precautions).

Parenteral drug products should wherever possible be visually inspected for particulate matter

and discoloration prior to administration.

Paediatric population: In the treatment of high dose indications, such as haematological,

rheumatic, renal and dermatological conditions, a dosage of 30 mg/kg/day to a maximum of

1 g/day is recommended. This dosage may be repeated for three pulses either daily or on

alternate days. In the treatment of graft rejection reactions following transplantation, a dosage of

10 to 20 mg/kg/day for up to 3 days, to a maximum of 1 g/day, is recommended. In the

treatment of status asthmaticus, a dosage of 1 to 4 mg/kg/day for 1-3 days is recommended.

Elderly patients: Solu-Medrol is primarily used in acute short-term conditions. There is no

information to suggest that a change in dosage is warranted in the elderly. However, treatment

of elderly patients should be planned bearing in mind the more serious consequences of the

common side-effects of corticosteroids in old age and close clinical supervision is required (see

section 4.4).

Detailed recommendations for adult dosage are as follows:

In anaphylactic reactions

adrenaline or noradrenaline should be administered first for an

immediate haemodynamic effect, followed by intravenous injection of Solu-Medrol

(methylprednisolone sodium succinate) with other accepted procedures. There is evidence that

corticosteroids through their prolonged haemodynamic effect are of value in preventing

recurrent attacks of acute anaphylactic reactions.

In sensitivity reactions

Solu-Medrol is capable of providing relief within one half to two hours.

In patients with status asthmaticus Solu-Medrol may be given at a dose of 40 mg

intravenously, repeated as dictated by patient response. In some asthmatic patients it

may be advantageous to administer by slow intravenous drip over a period of hours.

In graft rejection reactions following transplantation

doses of up to 1 g per day have been

used to suppress rejection crises, with doses of 500 mg to 1 g most commonly used for acute

rejection. Treatment should be continued only until the patient's condition has stabilised; usually

not beyond 48-72 hours.

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In cerebral oedema

corticosteroids are used to reduce or prevent the cerebral oedema

associated with brain tumours (primary or metastatic).

In patients with oedema due to tumour, tapering the dose of corticosteroid appears to be

important in order to avoid a rebound increase in intracranial pressure. If brain swelling

does occur as the dose is reduced (intracranial bleeding having been ruled out), restart

larger and more frequent doses parenterally. Patients with certain malignancies may

need to remain on oral corticosteroid therapy for months or even life. Similar or higher

doses may be helpful to control oedema during radiation therapy.

The following are suggested dosage schedules for oedemas due to brain tumour.

Schedule A (1)

Dose (mg)

Route

Interval

Duration

in hours

Pre-operative:

During Surgery:

20 to 40

hourly

Post operative:

24 hours

24 hours

24 hours

24 hours

24 hours

24 hours

24 hours

Schedule B (2)

Dose (mg)

Route

Interval

Days

in hours

Duration

Pre-operative:

Post-operative:

Oral

Oral

Oral

Oral

Oral

Aim to discontinue therapy after a total of 10 days.

REFERENCES

Fox JL, MD. "Use of Methylprednisolone in Intracranial Surgery" Medical

Annals of the District of Columbia, 34:261-265,1965.

Cantu RC, MD Harvard Neurological Service, Boston, Massachusetts. Letter on

file, The Upjohn Company (February 1970).

Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

4.3

Contraindications

Solu-Medrol is contraindicated:

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in patients who have systemic fungal infections unless specific anti-infective therapy is

employed and in cerebral oedema in malaria.

in patients with known hypersensitivity to methylprednisolone or to any of the

excipients

listed in section 6.1

Solu-Medrol 40mg: in patients with a known or suspected allergy to cow’s milk or its

components, or other dairy products, because it contains trace amounts of milk ingredients

(see section 4.4).

for use by the intrathecal route of administration.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving

immunosuppressive doses of corticosteroids.

4.4

Special 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 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.

Persons who are on drugs which suppress the immune system 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 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.

Similarly, 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.

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.

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If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close

observation is necessary as reactivation of the disease may occur. During prolonged

corticosteroid therapy, these patients should receive chemoprophylaxis.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy.

Discontinuation of corticosteroids may result in clinical remission.

Data from a clinical study conducted to establish the efficacy of Solu-Medrol in septic shock,

suggest that a higher mortality occurred in subsets of patients who entered the study with

elevated serum creatinine levels or who developed a secondary infection after therapy began.

Therefore, this product should not be used in the treatment of septic syndrome or septic shock.

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. A systematic

review of short-course, high-dose corticosteroids did not support their use. However, meta-

analyses, and a review suggest that longer courses (5-11 days) of low-dose corticosteroids might

reduce mortality, especially in patients with vasopressor-dependent septic shock.

Immune System Effects

Allergic reactions may occur. Rarely skin reactions and anaphylactic/anaphylactoid reactions

have been reported following parenteral Solu-Medrol therapy. Physicians using the drug should

be prepared to deal with such a possibility. Appropriate precautionary measures should be taken

prior to administration, especially when the patient has a history of drug allergy.

Cow’s milk allergy – Solu-Medrol 40mg/ml

Solu-Medrol 40mg/ml contains lactose monohydrate produced from bovine origin as an

excipient and may therefore contain trace amounts of cow’s milk proteins (the allergens of

cow’s milk). Serious allergic reactions, including bronchospasm and anaphylaxis, were reported

in patients allergic to cow’s milk proteins who were treated for acute allergic conditions.

Patients with known or suspected allergy to cow’s milk must not be administered Solu-Medrol

40mg/ml (see section 4.3).

Allergic reactions to cow’s milk proteins should be considered in patients receiving Solu-

Medrol 40mg/ml 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

40mg/ml should be stopped, and the patient’s condition should be treated accordingly.

Endocrine Effects

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly

acting corticosteroids before, during and after the stressful situation is indicated.

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.

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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. How dose reduction should be carried out depends largely on whether the

disease is likely to relapse as the dose of systemic corticosteroids is reduced. 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:

Patients who have had repeated courses of systemic corticosteroids, particularly if taken for

greater than 3 weeks.

When a short course has been prescribed within one year of cessation of long-term therapy

(months or years).

Patients who may have reasons for adrenocortical insufficiency other than exogenous

corticosteroid therapy.

Patients receiving doses of systemic corticosteroid greater than 32 mg daily of

methylprednisolone.

Patients repeatedly 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.

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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 and/or carers should be warned that potentially severe psychiatric adverse reactions

may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few

days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure

(see also section 4.5), 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. Patients/carers should be encouraged to seek medical

advice if worrying psychological symptoms develop, 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,

although such reactions have been reported infrequently.

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.

Frequent patient monitoring is necessary in patients with existing or previous history of severe

affective disorders (especially 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. (Also see

myopathy statement in Musculoskeletal Effects section). 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 (see section 4.8).

There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with

long-term use at high doses.

Ocular Effects

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. 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.

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Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear

cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may

result in glaucoma with possible damage to the optic nerves. Establishment of secondary fungal

and viral infections of the eye may also be enhanced in patients receiving glucocorticoids.

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 Solu-Medrol

(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 sodium

succinate, 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 (see section 4.8).

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

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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.

Osteoporosis is a common but infrequently recognized adverse effect associated with a long-

term use of large doses of glucocorticoid.

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 sodium succinate compared to

placebo. A causal association with methylprednisolone sodium succinate 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 (see section 4.5).

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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.

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.

For Solu-Medrol 500 mg & 1000 mg only:

Solu-Medrol 500 mg & 1000 mg contain Benzyl alcohol. I

ntravenous 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.

There is an increased risk due to accumulation in young children.

High volumes should be used with caution and only if necessary, especially in subjects with liver or

kidney impairment because of the risk of Benzyl alcohol accumulation and toxicity (metabolic acidosis).

4.5

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 (up-regulation) or inhibition of the

CYP3A4 enzyme.

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.

CYP3A4 INDUCERS - Drugs that induce CYP3A4 activity generally increase hepatic

clearance, resulting in decreased plasma concentration of medications that are substrates for

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CYP3A4. 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.

NON-CYP3A4-MEDIATED EFFECTS – Other interactions and effects that occur with

methylprednisolone are described in Table 2 below.

Table 2 provides a list and descriptions of the most common and/or clinically important drug

interactions or effects with methylprednisolone.

Table 2.

Important drug or substance interactions/effects with methylprednisolone

Drug Class or Type

- DRUG or

SUBSTANCE

Interaction

Effect

Macrolide Antibacterial

- TROLEANDOMYCIN

Antibacterial

- ISONIAZID

- GRAPEFRUIT JUICE

CYP3A4

INHIBITOR

CYP3A4 INHIBITOR.

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.

Antibiotic, Antitubercular

- RIFAMPIN

Anticonvulsants

- PHENOBARBITAL

- PHENYTOIN

CYP3A4

INDUCER

CYP3A4 INDUCER

A decrease in the plasma concentration of

methylprednisolone may occur.

Co-administration may require an increase

in methylprednisolone dosage to achieve

the desired result.

Antiemetic

- APREPITANT

- FOSAPREPITANT

Antifungal

- ITRACONAZOLE

- KETOCONAZOLE

Antivirals

- HIV-PROTEASE

INHIBITORS

Pharmacokinetic enhancers

- COBICISTAT

Calcium Channel Blocker

- DILTIAZEM

CYP3A4

INHIBITORS

(and

SUBSTRATES)

CYP3A4 INHIBITORS (and

SUBSTRATES)

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.

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Drug Class or Type

- DRUG or

SUBSTANCE

Interaction

Effect

Contraceptives (oral)

- ETHINYLESTRADIOL

/ NORETHISTERONE

Immunosuppressant

- CICLOSPORIN

Macrolide Antibacterial

- CLARITHROMYCIN

- ERYTHROMYCIN

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.

Anticonvulsants

- CARBAMAZEPINE

CYP3A4

INDUCER (and

SUBSTRATE)

CYP3A4 INDUCER (and SUBSTRATE)

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

Immunosuppressant

CYCLOPHOSPHAMIDE

- TACROLIMUS

CYP3A4

SUBSTRATES

CYP3A4 SUBSTRATES

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

Anticoagulants (oral)

Non-CYP3A4-

mediated effects

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. (See

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Drug Class or Type

- DRUG or

SUBSTANCE

Interaction

Effect

section 4.4, Musculoskeletal, for additional

information.)

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

AMINOGLUTETHIMID

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 anti-hypertensives.

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.

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Incompatibilities

To avoid compatibility and stability problems, it is recommended that methylprednisolone

sodium succinate be administered separately from other compounds that are administered via

the IV route of administration. Drugs that are physically incompatible in solution with

methylprednisolone sodium succinate include allopurinol sodium, doxapram hydrochloride,

tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium

bromide, cisatracurium besylate, glycopyrrolate and propofol (see section 6.2 for additional

information).

4.6

Fertility, pregnancy and lactation

Fertility

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

treatment with corticosteroids can lead to menstrual irregularities.

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however,

methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal

development including cleft palate, intra-uterine growth retardation and affects on brain growth

and development. There is no evidence that corticosteroids result in an increased incidence of

congenital abnormalities, such as cleft palate in man, however, when administered for long

periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine

growth retardation. Hypoadrenalism may, in theory, occur in the neonate following pre-natal

exposure to corticosteroids but usually resolves spontaneously following birth and is rarely

clinically important. Infants born to mothers, who have received substantial doses of

corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal

insufficiency. As with all drugs, corticosteroids should only be prescribed when the benefits to

the mother and child outweigh the risks. When corticosteroids are essential, however, patients

with normal pregnancies may be treated as though they were in the non-gravid state.

Since adequate human reproductive studies have not been done with methylprednisolone sodium

succinate, 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.

Breast-feeding

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.

4.7

Effects on ability to drive and use machines

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The effect of corticosteroids on the ability to drive or use machinery has not been systematically

evaluated.

Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are

possible after treatment with corticosteroids. If affected, patients should not drive or operate

machinery.

4.8

Undesirable effects

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 Solu-Medrol 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 (see section 4.4). Such side-effects

include:

MedDRA

System Organ Class

Frequency†

Undesirable Effects

Infections and infestations

Not Known

Infection (including increased susceptibility

and severity of infections with suppression

of clinical symptoms and signs);

Opportunistic infection; Recurrence of

dormant tuberculosis (see section 4.4),

Peritonitis

Neoplasms benign,

malignant and unspecified

(including cysts and

polyps)

Not Known

Kaposi’s sarcoma has been reported to occur

in patients receiving corticosteroid therapy.

Discontinuation of corticosteroids may result

in clinical remission.

Blood and lymphatic

system disorders

Not Known

Leukocytosis

Immune system disorders

Not Known

Drug hypersensitivity (Anaphylactic reaction

Anaphylactoid reaction)

Endocrine disorders

Not Known

Cushingoid; Hypopituitarism (including

suppression of the

hypothalamo-pituitary-adrenal axis), Steroid

withdrawal syndrome (including, fever,

myalgia, arthralgia, rhinitis, conjunctivitis,

painful itchy skin nodules and loss of

weight).

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Metabolism and nutrition

disorders

Not Known

Metabolic acidosis; Sodium retention; Fluid

retention; Glucose tolerance impaired;

Alkalosis hypokalaemic; Dyslipidemia,

Increased insulin requirements (or oral

hypoglycemic agents in diabetics);

Lipomatosis, Increased appetite (which may

result in weight increase); Epidural

lipomatosis

Psychiatric disorders

Not Known

A wide range of psychiatric reactions

including affective disorders (such as

irritable, euphoric, depressed and labile

mood drug dependence and suicidal

thoughts), psychotic reactions (including

mania, delusions, hallucinations and

schizophrenia), behavioural disturbances,

irritability, anxiety, sleep disturbances, and

cognitive dysfunction including confusion

and amnesia have been reported for all

corticosteroids. Reactions may occur in both

adults and children. In adults, the frequency

of severe reactions was estimated to be 5%-

6%. Psychological effects have been

reported on withdrawal of corticosteroids;

the frequency is unknown.

Nervous system disorders

Not Known

Increased intracranial pressure with

Papilloedema [Benign intracranial

hypertension]; Seizure; Amnesia; Cognitive

disorder; Dizziness; Headache

Eye disorders

Rare

Vision blurred (see also section 4.4).

Not Known

Posterior subcapsular cataracts;

Exophthalmos; Glaucoma; Papilloedema

with possible damage to the optic nerve;

Corneal or scleral thinning; Exacerbation of

ophthalmic viral or fungal disease;

Chorioretinopathy.

Ear and labyrinth

disorders

Not Known

Vertigo

Cardiac disorders

Not Known

Congestive heart failure in susceptible

patients, Arrhythmia

Vascular disorders

Not Known

Hypertension; Hypotension; Thrombotic

events.

Respiratory, thoracic and

mediastinal disorders

Not Known

Hiccups; Pulmonary embolism.

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Gastrointestinal disorders

Not Known

Peptic ulcer (with possible peptic ulcer

perforation and peptic ulcer haemorrhage);

Gastric haemorrhage; Intestinal perforation;

Pancreatitis; Ulcerative oesophagitis;

Oesophagitis; Oesophageal candidiasis;

Abdominal pain; Abdominal distension;

Diarrhoea; Dyspepsia; Nausea; Vomiting;

Bad taste in mouth may occur especially

with rapid administration

Hepatobiliary disorders

Not Known

Hepatitis†; Increase of liver enzymes (e.g

alanine aminotransferase increased (ALT,

SGPT), aspartate aminotransferase increased

(AST, SGOT)).

Skin and subcutaneous

tissue disorders

Not Known

Ecchymosis; Skin atrophy (thin fragile skin);

Acne; Angioedema; Petechiae; Skin striae;

Telangiectasia; Skin hypopigmentation or

hyperpigmentation; Hirsutism; Rash;

Erythema; Pruritus; Urticaria; Hyperhidrosis

Musculoskeletal and

connective tissue disorders

Not Known

Growth retardation; Osteoporosis; Muscular

weakness; Osteonecrosis; Pathological

fracture; Muscle atrophy; Myopathy;

Neuropathic arthropathy; Arthralgia;

Myalgia

Reproductive system and

breast disorders

Not Known

Irregular menstruation; Amenorrhoea

General disorders and

administration site

conditions

Not Known

Impaired wound healing; Oedema

peripheral; Injection site reaction; Fatigue;

Malaise; Withdrawal symptoms - Too rapid

a reduction of corticosteroid dosage

following prolonged treatment can lead to

acute adrenal insufficiency, hypotension and

death. However, this is more applicable to

corticosteroids with an indication where

continuous therapy is given (see Section 4.4)

Investigations

Not Known

Intraocular pressure increased; Carbohydrate

tolerance decreased; Blood potassium

decreased (potassium loss); Urine calcium

increased; Blood alkaline phosphatase

increased; Blood urea increased;

Suppression of reactions to skin tests

Injury, poisoning and

procedural complications

Not Known

Tendon rupture (particularly of the Achilles

tendon); Spinal compression fracture

(vertebral compression fractures)

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Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000);

Not known (frequency cannot be estimated from the available data)

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

# Peritonitis may be the primary presenting sign or symptom of a gastrointestinal disorder such

as perforation, obstruction or pancreatitis (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.Any

suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form https://sideeffects.health.gov.il/

4.9

Overdose

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticoids, ATC code: H02AB04

Methylprednisolone is a corticosteroid with an anti-inflammatory activity at least five times that

of hydrocortisone.

An enhanced separation of glucocorticoid and mineralocorticoid effect results in a reduced

incidence of sodium and water retention.

5.2

Pharmacokinetic properties

Methylprednisolone pharmacokinetics is linear, independent of route of administration.

Distribution:

Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is

secreted 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%.

Metabolism:

Methylprednisolone is extensively bound to plasma proteins, mainly to globulin and less so to

albumin. Only unbound corticosteroid has pharmacological effects or is metabolised.

Metabolism occurs in the liver and to a lesser extent in the kidney. In humans,

methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-

hydroxymethylprednisolone and 20β-hydroxymethylprednisolone.

Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based

on CYP3A4-mediated metabolism, see section 4.5).

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Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-

binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and

interactions with other medicines.

Elimination:

Metabolites are excreted in the urine.

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.

Mean elimination half-life ranges from 2.4

to 3.5 hours in normal healthy adults and appears to be independent of the route of

administration.

Total body clearance following intravenous or intramuscular injection of methylprednisolone to

healthy adult volunteers is approximately 15-16 L/hour. Peak methylprednisolone

plasma levels of 33.67 micrograms/100 ml were achieved in 2 hours after a single 40 mg

I.M. injection to 22 adult male volunteers.

5.3

Preclinical safety data

Based on conventional studies of safety pharmacology and repeated dose toxicity, no

unexpected hazards were identified. The toxicities seen in the repeated-dose studies were those

expected to occur with continued exposure to exogenous adrenocortical steroids.

Mutagenic potential:

Methylprednisolone has not been formally evaluated for genotoxicity. Studies using structurally

related analogues of methylprednisolone showed no evidence of a potential for genetic and

chromosome mutations in limited studies in bacteria and mammalian cells.

Carcinogenic potential:

Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable

results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats.

However, published data indicate that several related glucocorticoids including budesonide,

prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular

adenomas and carcinomas after oral administration in drinking water to male rats. These

tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m

basis. The clinical relevance of these findings is unknown.

Reproductive toxicity:

Methylprednisolone has not been evaluated in animal fertility studies. Corticosteroids have been

shown to reduce fertility when administered to rats. Adverse effects on fertility in male rats

administered corticosterone were observed and were reversible. Decreased weights and

microscopic changes in prostate and seminal vesicles were observed. The numbers of

implantations and live fetuses were reduced and these effects were not present following mating

at the end of the recovery period.

An increased frequency of cleft palate was observed among the offspring of mice treated during

pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in

humans.

An increased frequency of cardiovascular defects and decreased body weight were observed

among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar

to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic

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effect was noted in rats with doses <1-18 times those typically used for oral therapy in humans

in another study. High frequencies of foetal death and a variety of central nervous system and

skeletal anomalies were reported in the offspring of pregnant rabbits treated with

methylprednisolone in doses less than those used in humans. The relevance of these findings to

the risk of malformations in human infants born to mothers treated with methylprednisolone in

pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Act-O-Vial System (Single Dose Vial)

SOLU-MEDROL

®

Sterile Powder 40 mg:

Each 1 ml Act-O-Vial contains:

I. Powder compartment: Lactose, Dibasic sodium phosphate dried, Monobasic sodium

phosphate monohydrate, Sodium hydroxide, Water for injection

II. Diluent compartment: Water for injection

SOLU-MEDROL

®

Sterile Powder 125 mg:

Each 2 ml Act-O-Vial contains:

I. Powder compartment: Dibasic sodium phosphate Dried,

Monobasic sodium phosphate monohydrate, Sodium hydroxide, Water for injection

II. Diluent compartment: Water for injection

Vial with Diluent

SOLU-MEDROL

®

Sterile Powder 500 mg:

I. Each powder vial contains: Dibasic sodium phosphate dried, Monobasic sodium phosphate

monohydrate, Sodium hydroxide, Water for injection

II. Each diluent vial (8 ml) contains: Benzyl alcohol, Water for injection

SOLU-MEDROL

®

Sterile Powder 1000 mg:

I. Each powder vial contains: Dibasic sodium phosphate dried, Monobasic sodium phosphate

monohydrate, Sodium hydroxide, Water for injection

II. Each diluent vial (16 ml) contains: Benzyl alcohol, Water for injection

Solu-Medrol 500 mg & 1000 mg contain Benzyl alcohol

(see Section 4.4 Special warnings and

precautions for use)

6.2

Incompatibilities

6.3

Shelf-life

The expiry date of the product is indicated on the packaging materials.

Solu-Medrol LPD CC 080920

Page 25 of 26

2020-0060629

SOLU-MEDROL

®

Sterile Powder 40mg, 125 mg, 500 mg and 1000mg: After reconstitution

with the diluents provided: Chemically, the product is stable for 12 hours at a temperature of

25ºC. In the aspect of microbiology, the product should be used immediately.

6.4

Special precautions for storage

Store below 25°C.

Refer to Section 6.6. No diluents other than those referred to are recommended. Parenteral drug

products should be inspected visually for particulate matter and discoloration prior to

administration.

6.5

Nature and contents of container

Act-O-Vial System (Single-Dose Vial)

Hydrolytic glass class I Act-O-Vial with Halobutyl rubber stoppers.

Each Act-O-Vial of Solu-Medrol 40 mg contains the equivalent of 40 mg of methylprednisolone

as the sodium succinate (Powder compartment) for reconstitution with 1 ml of Water for

Injections (Diluent compartment).

Each Act-O-Vial of Solu-Medrol 125 mg contains the equivalent of 125 mg of

methylprednisolone as the sodium succinate (Powder compartment) for reconstitution with 2 ml

of Water for Injections (Diluent compartment).

Vial with Diluent

1 Powder vial+1 Diluent vial: glass class I vials with butyl rubber plug and flip top seals.

Each vial of Solu-Medrol 500 mg contains the equivalent of 500 mg of methylprednisolone as

the sodium succinate for reconstitution with 8 ml of Bacteriostatic Water for Injections.

Each vial of Solu-Medrol 1000 mg contains the equivalent of 1000 mg of methylprednisolone as

the sodium succinate for reconstitution with 16 ml of Bacteriostatic Water for Injections.

6.6

Special precautions for disposal and other handling

Precautions for disposal:

No special requirement.

Directions for use:

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 tab covering center of stopper.

4. Sterilize top of stopper with a suitable germicide.

5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and

withdraw dose.

Directions for Use of the Vial

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

diluent.

Solu-Medrol LPD CC 080920

Page 26 of 26

2020-0060629

Preparation of Solutions -

To prepare solutions for intravenous infusion, first reconstitute methylprednisolone sodium

succinate as directed. Therapy may be initiated by administering methylprednisolone sodium

succinate intravenously over a period of at least five minutes (e.g, doses up to 250 mg) to at

least 30 minutes (e.g, doses of 250 mg or more). 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.

7. MANUFACTURER

Pfizer Manufacturing Belgium NV/SA, Puurs, Belgium.

8. LICENSE HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzeliya Pituach 46725

9

LICENSE NUMBER:

SOLU-MEDROL

40 mg: 025-48-22223

SOLU-MEDROL

125 mg: 126-13-20236

SOLU-MEDROL

500 mg: 114-09-22488

SOLU-MEDROL

1000 mg: 114-10-22489

Revised in 09/2020

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