Special Warning : אזהרת שימוש

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 
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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.

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 Methylprednisolonein 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 Methylprednisolonetherapy. 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.


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.

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.

Page 9 of 27                               2024-0091167 ; 2024-00935426 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.

Thyrotoxic Periodic Paralysis (TPP) can occur in patients with hyperthyroidism and with methylprednisolone-induced hypokalaemia.

TPP must be suspected in patients treated with methylprednisolone presenting signs or symptoms of muscle weakness, especially in patients with hyperthyroidism.

If TPP is suspected, levels of blood potassium must be immediately monitored and adequately managed to ensure the restoration of normal levels of blood potassium.


Page 10 of 27                              2024-0091167 ; 2024-00935426 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.


Page 11 of 27                              2024-0091167 ; 2024-00935426 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 Methylprednisolone (greater than 500 mg administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone 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
Page 12 of 27                            2024-0091167 ; 2024-00935426 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).


Page 13 of 27                                2024-0091167 ; 2024-00935426 The lowest possible dose of corticosteroid should be used to control the condition under treatment and when reduction in dosage is possible, the reduction should be gradual.

Aspirin and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

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

Severe medical events have been reported in association with the intrathecal/epidural routes of administration. There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.

Paediatric population:

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

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

High doses of corticosteroids may produce pancreatitis in children.

Hypertrophic cardiomyopathy may develop after administration of methylprednisolone to prematurely born infants, therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure should be performed.

Excipient information

For Solu-Medrol 40 mg & 125 mg:
Solu-Medrol 40 mg & Solu-Medrol 125 mg contains less than 1 mmol sodium (23 mg) in each vial, that is to say essentially ‘sodium- free’.

For Solu-Medrol 500 mg & 1000 mg:
Solu-Medrol 500 mg contains 58.39 mg of sodium in each vial, equivalent to 2.92% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Solu-Medrol 1 g contains 116.78 mg of sodium in each vial, equivalent to 5.84% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Solu-Medrol 500 mg & 1000 mg diluent contain 0.9% Benzyl alcohol. 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.
There is an increased risk due to accumulation in young children.

Page 14 of 27                               2024-0091167 ; 2024-00935426 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).

Effects on Driving

4.7    Effects on ability to drive and use machines

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.