METHYLPREDNISOLONE 40 MG POWDER FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Methylprednisolone 40 mg

Powder for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of Methylprednisolone 40 mg contains 53.0 mg of methylprednisolone sodium succinate, equivalent to 40 mg of methylprednisolone.

Excipient with known effect: This presentation contains less than 1 mmol sodium (23mg) per 40mg, i.e. essentially “sodium-free”.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

Each vial of methylprednisolone sodium succinate contains a white or nearly white amorphous powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Methylprednisolone is indicated to treat any condition in which rapid and intense corticosteroid effect is required such as:

Allergic states:

Bronchial asthma

Severe seasonal and perennial allergic rhinitis

Angioneurotic oedema

Anaphylaxis

Dermatologic diseases:

Severe erythema multiforme (Stevens-Johnson syndrome).

Gastrointestinal diseases:

Crohn’s disease

Ulcerative colitis.

Neurological disorders:

Acute exacerbations of multiple sclerosis superimposed on a relapsing-remitting background

Secondary cerebral oedema caused by cerebal tumour

Respiratory diseases:

Aspiration of gastric contents

Fulminat or disseminated pulmonary tuberculosis (with appropriate antituberculosis chemotherapy)

Miscellaneous:

T.B.C. meningitis (with appropriate anti-tuberculosis chemotherapy)

Transplantation

4.2 Posology and method of administration

Methylprednisolone may be administered intravenously or intramuscularly, the preferred method for emergency use being intravenous injection given over a suitable time interval.

Posology

When Methylprednisolone is administered in high doses intravenously, it should be given over a period of at least 30 minutes. Doses up to 250 mg should be given intravenously over a period of at least five minutes.

Undesirable effects may be minimized by using the lowest effective dose for the minimum period (see Section 4.4).

Adults

Dosage should be varied according to the severity of the condition, the initial dose should be between 10 to 500 mg. In the treatment of graft rejection reactions following transplantation, a dose of up to 1 g/day may be required. Although doses and protocols have varied in studies using methylprednisolone sodium succinate in the treatment of graft rejection reactions, the published literature supports the use of doses of this level, with 500 mg to 1 g most commonly used for acute rejection.

Treatment at these doses should be limited to a 48–72 hours period until the patient’s condition has stabilized, as prolonged high dose corticosteroid therapy can cause serious corticosteroid induced side effects (see Sections 4.4 and 4.8).

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 in three consecutive cycles on a daily basis or on every second day. 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 asthmatic states, a dosage of 1 to 4 mg/kg/day for 1 – 3 days is recommended.

Elderly patients:

Methylprednisolone 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 Methylprednisolone (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 Methylprednisolone is capable of providing relief of symptoms within half to two hours. In patients with status asthmaticus Methylprednisolone may be given at a dose of 40 mg intravenously, repeated as dictated by the patient response. In some asthmatic patients it may be of advantage to administer the product as a slow drop infusion over a time period of several hours.

In graft rejection reactions following transplantation doses of up to 1 g per day have been used to suppress rejection crises. In case of acute rejection, doses of 500 mg to 1 g are commonly used. Treatment should be continued only until the patient’s condition has stabilized; usually not beyond 48–72 hours.

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 malignant diseases may need to remain on oral corticosteroid therapy for months or even life. Similar or higher doses may be helpful to control cerebral oedema during radiation therapy.

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

In other indications, initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short term management of severe, acute conditions. The initial dose, up to 250 mg, should be given intravenously over a period of at least 5 minutes, doses exceeding 250 mg should be given intravenously over a period of at least 30 minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition. Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

For instruction on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The usual contra-indications to the systemic or local use of corticosteroids should be observed. Methylprednisolone is contra-indicated in systemic fungal infection and in systemic infection unless specific anti-infective therapy is employed. For intrathecal administration, since reports of severe medical events have been associated with this route of administration. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Cerebral oedema associated with malaria.

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of interaction

Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

Immunosuppressants, as methotrexate, may have synergistic effect on disease state which may allow to reduce dose of corticosteroid.

Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced. It may be necessary to increase the Methylprednisolone dose to achieve the desired response.

Drugs that inhibit the cytochrome P450 enzymatic system (particularly CYP3A4), such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity.

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.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensive and diuretic drugs are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal antiinflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.

Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular bloc­k.

Antipsychotics can cause recurrence or poor control of CNS symptoms, when used with methylprednisolone, which may require a dose adjustment.

Sympathomimetic agents, as salbutamol, can increase the efficacy and potentially increase toxicity by increased response to sympathetic agents, when used with methylprednisolone.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies have shown that high corticosteroid doses to pregnant females may cause foetal malformations. However, corticosteroids do not appear to cause congenital malformations when given to pregnant women. Despite this, methylprednisolone sodium succinate should be used during pregnancy in critical cases only as studies in humans cannot establish the safety of the product during use in pregnancy.

Some corticosteroids cross the placenta easily. In a retrospective study, an increased frequency of low birth-weight was observed in children whose mothers had been using corticosteroids. Although adrenal insufficiency is rare in children who have been exposed to corticosteroids in utero, children exposed to high corticosteroid doses should be monitored carefully and examined for the risk of adrenal insufficiency.

The effect of corticosteroids on delivery is not known.

Cataract has been observed in neonates whose mothers have received long-term corticosteroid treatment during pregnancy.

Breastfeeding

Corticosteroids are excreted in breast milk.

Corticosteroids excreted in breast milk can suppress the growth of breast-fed infants and disturb endogenous production of glucocorticoids. As reproduction studies with corticosteroids in humans are inadequate, corticoids should be used in lactating mothers only if the benefit from the treatment is assessed greater than the possible risks to the child.

The possible benefits of corticosteroid medication must be weighed against possible adverse effects to the mother and embryo or foetus before giving this medicinal product to pregnant or lactating women, or to women of fertile age.

Fertility

There is no evidence that corticosteroids would impair fertility.

4.7 Effects on ability to drive and use machines

The effect of Methylprednisolone 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

Under normal circumstances Methylprednisolone 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:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

*Scleroderma renal crisis

Amongst the different subpopulations the occurrence of scleroderma renal crisis varies. The highest risk has been reported in patients with diffuse systemic sclerosis. The lowest risk has been reported in patients with limited systemic sclerosis (2%) and juvenile onset systemic sclerosis (1%)

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Reports of acute toxicity and metabolic disturbances with glucocorticoids are rare but do occur. There is no clinical syndrome of acute overdosage with Methylprednisolone. Acute overdose may possibly aggravate pre-existing disease states such as ulceration of the gastrointestinal tract, electrolyte disturbances, infections, diabetes and oedema. Repeated high doses of methylprednisolone have caused hepatic necrosis and an increase in amylase. Bradyarrhythmias, ventricular arrhythmias and cardiac arrest have been observed in cases of intravenous administration of high doses of methylprednisolone.

Repeated frequent doses (daily or several times per week) over a protracted period may result in a Cushingoid state. The possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In the event of an overdose, no specific antidote is available; treatment is symptomatic and supportive, including respiratory and cardiovascular function. In chronic toxicity, fluids and electrolytes should be monitored closely. Serum levels are not clinically useful. Methylprednisolone is dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Corticosteroids for Systemic Use; ATC: H02AB04.

Methylprednisolone is a potent anti-inflammatory steroid. It has a greater antiinflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention. Its anti-inflamatory activity is at least five times that of hydrocortisone.

Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and 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.

Absorption

After an intravenous infusion of Methylprednisolone, 30mg/kg over a 20 minute period or 1g over 30 to 60 minutes, peak methylprednisolone plasma concentrations of approximately 20^ig/mi were achieved. Peak methylprednisolone levels of 42–47^ig/100mi were reported following a single 40mg IV bolus injection to six adult male volunteers

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.

Metabolites are excreted in the urine.

Peak methylprednisolone plasma levels of 33.67 ^g/100ml were achieved in two hours after a single 40 mg IM injection to 22 adult male volunteers. Although with intramuscular (IM) injection lower peak levels are obtained than with intravenous (IV) injection, the plasma levels persist longer such that the extent of methylprednisolone absorption is equivalent with either route of administration.

Distribution

Methylprednisolone is widely distributed throughout the body and is described by a two-compartment model. Its apparent volume of distribution is approximately 1.4 ml/kg and its total clearance is approximately 5 to 6ml/min/kg.

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.

Methylprednisolone readily crosses the blood-brain barrier into the central nervous system with peak CSF levels being 5 – 6% of the corresponding plasma levels.

Methylprednisolone peak CSF levels occurred within five minutes to one hour after IV administration of a 500 mg dose to patients with lupus cerebritis.

Methylprednisolone and its sodium succinate salt cross the placental barrier. Although there is no data regarding methylprednisolone passage into breast milk of humans, it is present in breast milk of animals.

Biotransformation

Methylprednisolone, the sodium succinate ester of methylprednisolone, is rapidly and extensively hydrolysed in vivo by cholinesterases to free methylprednisolone. In humans, methylprednisolone is metabolised in the liver to inactive metabolites, the major ones being 20p-hydroxymethyi­prednisone and 20 a-hydroxy-6-amethylprednisone. Metabolism in the liver occurs primarily via the CYP3A4. (For a iist of drug interactions based on CYP3A4-mediated metaboiism (see Section 4.5).

Elimination

The mean eiimination haif-iife ranges for totai methyiprednisoione is in the range of 1.8 to 5.2 hours.

The piasma protein binding of methyiprednisoione in humans is approximateiy 77%. Totai body ciearance foiiowing intravenous or intramuscuiar injection of methylprednisolone to healthy adult volunteers is approximately 15 – 16l/hr. In adult voiunteers receiving 40 mg Methyiprednisoione, either IM or IV, renai ciearance is 0.61 – 0.83l/hr. Methylprednisolone clearance is altered by concurrent administration of troleandomycin, erythromycin, rifampin, anti-convulsants, and theophylline.

Following IV administration of radiolabelled 6a-methyl-prednisolone to six cancer patients, 75% of total reactivity was recovered in the urine after 96 hours and 9% in the faeces after five days. Twenty percent of the total dose was excreted in the bile, but the time course was not cited.

5.3 Preclinical safety data

Non-clinical data reveal no unexpected hazards for mice, rats, rabbits and dogs based on conventional studies of safety pharmacology and repeated dose toxicity with intravenous, intraperitoneal, subcutaneous, intramuscular, and peroral administration.

Methylprednisolone is a potent steroid the pharmacological effects of which are comparable to those of glucocorticoids, including the effects on carbohydrate metabolism, electrolyte and fluid balance, blood cells, lymphatic tissue and protein metabolism, which can lead to reduction or cessation of weight gain, lymphopenia, and atrophy of the spleen, thymus, lymph nodes, adrenal cortex and testes as well as fatty liver, and hyperplasia of pancreatic islet cells. A 30 day study on reversibility in rats which had received methylprednisolone showed that the vital functions returned to normal after about 1 month from discontinuing the drug. Following a 52-week-long administration of methylprednisolone suleptanate to rats, many parameters returned to normal after a 9 week period of reversibility. Toxicities detected in studies with repeated dosage are those that can be expected after continuous exposure to exogenous adrenocortical steroids.

Carcinogenicity

No long-term studies in animals have been done to assess carcinogenicity as the drug substance is meant for short-term use only, and no signs of a carcinogenic effect have been detected. There is no evidence of carcinogenicity of corticosteroids.

Mutagenicity

In DNA damage determination by the alkaline elution technique in V79 cells of the Chinese hamster, no evidence on genetic or chromosomal mutations was obtained. Methylprednisolone did not cause chromosomal damage without the hepatic activation system.

Reproduction toxicity

No teratogenic effects in mice or rats were detected in animal studies on embryotoxic effects of methylprednisolone at the intraperitoneal daily dose of 125 mg/kg/day to mice and 100 mg/kg/day to rats. In rats, methylprednisolone was teratogenic when less than 20 mg/kg/day was given subcutaneously. Methylprednisolone aseponate was teratogenic in rats when less than 1.0 mg/kg/day was given subcutaneously.

Animal data are insufficient with respect to fertility.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium di-hydrogen phosphate dihydrate

Disodium phosphate anhydrous

Sodium hydroxide

The 40 mg vial also contains glucose.

6.2 Incompatibilities

To avoid compatibility problems with other drugs Methylprednisolone should be administered separately, only in the solutions mentioned in Section 6.6.

6.3 Shelf life

2 years

After reconstitution as recommended, use immediately, discard any remainder.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° to 8°C, unless reconstitution/di­lution has taken place in controlled and validated aseptic conditions

6.4 Special precautions for storage

Store below 25°C.

Keep the vial in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

Type I clear glass vial with type I bromobutyl rubber stopper and flip-off aluminium cap.

Packs of 1 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

a) Preparation of solution for injection (reconstitution):

Methylprednisolone solution for injection should be prepared by dissolving the powder in an appropriate volume of water for injection, as shown in the table below.

b) Preparation of infusion solution

For intravenous infusion the initially prepared solution may be diluted with 5% dextrose in water for injection, 0.9% Sodium Chloride in water for injection (isotonic saline solution), or 5% dextrose in isotonic saline solution. To avoid compatibility problems with other drugs Methylprednisolone should be administered separately, only in the solutions mentioned.

Parenteral drugs products should be inspected visually for particulate matter and discoloration prior to administration.

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

7 MARKETING AUTHORISATION HOLDER

Hikma Farmaceutica (Portugal), S.A.

Estrada do Rio da Mo 8, 8A e 8B – Fervenca

2705–906 Terrugem

Portugal

portugalgeral@hik­ma.com

8 MARKETING AUTHORISATION NUMBER(S)

PL 15413/0027