Summary of medicine characteristics - METHYLPREDNISOLONE 1000 MG POWDER AND SOLVENT FOR SOLUTION FOR INJECTION/INFUSION
Methylprednisolone 1000 mg powder and solvent for solution for injection/infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial of powder contains methylprednisolone sodium succinate 1326.0 mg equivalent to 1000 mg of methylprednisolone. After reconstitution in water for injections, each ml of solution contains the equivalent of 59.6 mg of methylprednisolone.
Each vial of solvent contains 15.6 ml of water for injections.
Sodium content: the 1000 mg methylprednisolone vials contain the equivalent of 74.4 mg (3.2 mmol) of sodium.
For a full list of excipients, see section 6.1
Powder and solvent for solution for injection/infusion.
Each vial of methylprednisolone sodium succinate contains a white or almost white amorphous powder.
Each vial of solvent contains water for injections.
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
Methylprednisolone powder for injection/infusion is contraindicated:
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
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 presentations 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. Chickenpox 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 the 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 septicaemia. Although
Methylprednisolone is not approved in the UK for use in any shock indication, the following warning statement should be adhered to. Data from a clinical study conducted to establish the efficacy of methylprednisolone 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 syndromes 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
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.
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.
Allergic reactions may occur. Rarely skin reactions and anaphylactic/anaphylactoid reactions have been reported following parenteral methylprednisolone 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.
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroid before, during and after stressfull situation is indicated.
Pharmacological 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 an alternate-day therapy.
In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly.
In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt.
Drug-induced secondary adrenocortical insufficiency may therefore be minimised by the 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 corticosteroids 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 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 longterm therapy (months or years).
Patients who may have reasons for adrenocortical insufficiency otherthan exogenous corticosteroid therapy.
Patients receiving doses of systemic corticosteroid greater than 32 mg dailyof methylprednisolone.
Patients repeatedly taking doses in the evening.
Patients should carry ‘Steroid Treatment’ cards which can give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and duration of treatment.
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 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.
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.
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).
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 below). 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 longterm use at high doses.
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.
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 alternated 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).
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.
High doses of corticosteroids may produce acute pancreatitis.
There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy, however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or haemorrhage may occur without significant pain. Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis.
In combination with NSAIDs, the risk of developing gastrointestinal ulcers is increased.
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is
necessary:
Ulcerative colitis
Perforation, Abscess or other pyogenic infections
Diverticulitis
Fresh intestinal anastomoses
Peptic ulceration
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.
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 recognised adverse effect associated with long-term use of large doses of glucocorticoid.
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.
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 synthetic derivatives except when used in large doses.
Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury, a multicenter study revealed an increase in 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.
Since complications of treatment with glucocorticoids are dependent on the size of the dose and 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).
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 antiflammatory 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.
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.
This medicinal product contains 74.4 mg (3.2 mmol) sodium per 1000 mg, equivalent to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
4.5 Interaction with other medicinal products and other forms of interaction
Methylprednisolone is a cytochrome P450 enzyme (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 catalyzes 6P-hydroxylation of steroids, the essential Phase 1 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 (upregulation) 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.. 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 effects. 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 CYP3A4. Coadministration 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 coadministration.
NON-CYP3A4 – MEDIATED EFFECTS – Other interactions and effects that occur with methylprednisolone are described in Table 2 below. Table 2 provides a list and description of the most common and/or clinically important drug interactions or effects with methylprednisolone.
Table 2. Important drug or substrate interactions/effects with methylprednisolone
| Drug Class or Type – DRUG or SUBSTANCE | Interaction | Effect |
| Macrolide Antibacterial – TROLAENDOMYCIN Antibacterial – ISONIAZID – COBICISTAT-CONTAINING PRODUCTS – – GRAPEFRUIT JUICE | CYP3A4 INHIBITOR | CYP3A4 INHIBITOR An increase in the plasma concentration of methylprednisolone may occur. The dose ol methylprednisolone may need to be treated steroid toxicity. In addition, there is a potential effect of methylprednisolone to increase the acetylati 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-adminis may require an increase in methylprednisolc dosage to achieve the desired result. |
| Antiemetic -APREPITANT – FOSAPREPITANT Antifungal – ITRACONAZOLE – KETOCONAZOLE Antivirals -HIV-PROTEASE INHIBITORS Pharmacokinetic enhancers -COBICISTAT Calcium Channel Blocker -DILTIAZEM Contraceptives (oral) – ETHINYLESTRADIOL/ NORETHISTERONE Immunosuppressant -CICLOSPORIN Macrolide Antibacterial -CLARITHROMYCIN -ERYTHROMYCIN | CYP3A4 INHIBITORS (and SUBSTRATES) | CYP3A4 INHIBITORS (and SUBSTRATE The hepatic clearance of methylprednisolon inhibited or induced, resulting in an increasi decrease in the plasma concentration of methylprednisolone. A corresponding dosag adjustment may be required. It is possible th adverse events associated with the use of eil alone may be more likely to occur with administration. 1) Protease inhibitors, such as indinavir a ritonavir, may increase plasma concentr corticosteroids. 2) Corticosteroids may induce the metabol HIV protease inhibitors resulting in redi plasma concentrations. Ciclosporin 1) Mutual inhibition of metabolism occurs \ concurrent use of ciclosporin and methylprednisolone, which may increase th concentrations of either or both drugs. Ther possible that adverse events associated with of either drug alone may be more likely to c upon coadministration. 2) Convulsions have been reported with con use of methylprednisolone and ciclosporin. |
| Anticonvulsants – CARBAMAZEPINE | CYP3A4 INDUCER (and SUBSTRA TE) | 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 SUBSTR ATES | 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 section 4.4 Warnings and Precautions, 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. | |
| Antidiabetics | Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required | |
| Aromatase inhibitors -AMINOGLUTETHIMIDE | Aminoglutethimide-induced adrenal suppression may impede endocrine changes caused by prolonged glucocorticoid treatment. |
| NSAIDs (nonsteroidal antiinflammatory 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 3) methylprednisolone treatment can lead to raised 4) 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 hypokalemia. Corticosteroids antagonise 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 antagonise the hypotensive effect of all antihypertensives. There is an increased risk of hypokalaemia when corticosteroids are given with cardiac glycosides.
The effects of corticosteroids may be reduced for 3–4 days after mifepristone.
Incompatibilities
To avoid compatibility and stability problems, it is recommended that methylprednisolone 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, but are not limited to: 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 effects 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 prenatal 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 corticosteroidsare 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 the 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
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 Methylprednisolone powder for injection/infusion 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 sideeffects 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 | Leucocytosis |
| Immune system disorders | Not known | Drug hypersensitivity (Anaphylactic reaction and Anaphylactoid) |
| 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) |
| Metabolism and nutrition disorders | Not known | Metabolic acidosis; Sodium retention; fluid retention; Glucose tolerance impaired; alkalosis hypokalaemic; dyslipidemia; increased insulin requirements (or oral hypoglycaemic agents in diabetics) increased appetite (which may result in weight increased), lipomatosis; epidural lipomatosis. |
| Psychiatric disorders | Not known | A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile moods drug dependence and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and schizophrenia), behavioural disturbances , irritability, anxiety, sleep disturbances andcognitive dysfunction including confusion and amnesia have been reported for all corticosteroids. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions was estimated to be a 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, convulsion, amnesia, cognitive disorder; dizziness; headache |
| Eye disorders | Not known | Posterior subcapsular cataracts ,Exophthalmos; glaucoma; papilloedema with possible damage to the optic nerve, corneal or scleral thinning; chorioretinopathy; exacerbation of ophthalmic viral or fungal disease |
| Rare | Vision blurred (see also section 4.4) | |
| Ear and labyrinth disorders | Not known | Vertigo |
| Cardiac disorders | Not known | Congestive heart failure in susceptible patients, arrhythmia |
| Vascular disorders | Not known | Hypertension ,Hypotension; thromboembolism; thrombotic events |
| Respiratory, thoracic and mediastinal disorders | Not known | Hiccups; pulmonary embolism. |
| Gastrointestina l 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 f; 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 |
| Musculoskeleta l and connective tissue disorders | Not known | Growth retardation (in children); 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 | Blood potassium decreased (potassium loss), Blood alkaline phosphatase increased; Blood urea increased; intraocular pressure increased; carbohydrate tolerance decreased; urine calcium 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) |
fCommon (>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)
fHepatitis has been reported with IV administration (see section 4.4).
#Peritonitis may be the primary presenting sign or symptom of gastrointestinal disorder such as perforation, obstruction or pancreatitis (see section 4.4).
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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
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 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 metabolised in the liver to inactive metabolites; the major ones are 20 □hydroxymethylprednisolone and 200-hydroxymethylprednisolone.
Metabolism in the liver occurs 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 the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribtion 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. Its 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 15–16l/hour. Peak methylprednisolone plasma levels of 33.67 mcg/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
5.3 Preclinical safety dataBased 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/m2 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 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
Sodium phosphate dibasic.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3. Shelf life
Shelf-life of the medicinal product as packaged for sale: 2 years.
After reconstitution with Sterile Water for Injections, use immediately, discard any remainder.
6.4 Special precautions for storage
This product does not require any special temperature storage conditions.
Keep the vials in the outer carton in order to protect from light.
6.5 Nature and contents of container
Powder
Type I clear glass vial with butyl rubber plug and flip top seal.
Each vial contains the equivalent of 1000 mg of methylprednisolone as the sodium succinate for reconstitution with 15.6 ml of Water for Injections.
Solvent
Type I clear glass vial with butyl rubber plug and flip top seal.
Each vial contains 15.6 ml of Water for Injections.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAfter reconstitution, the solution should be clear and colourless. Parenteral drug products should wherever possible be visually inspected for particulate matter and discoloration prior to administration.
The initially prepared solution may be diluted with 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution. To avoid compatibility problems with other drugs, the reconstituted methylprednisolone solution should be administered separately, only in the solutions mentioned.
Beacon Pharmaceuticals Limited, The Bower, 4 Roundwood Avenue, Stockley Park, Heathrow, United Kingdom, UB11 1AF.
8 MARKETING AUTHORISATION NUMBER(S)
PL 18157/0228
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
07/06/2011