SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Depo-Medrone 40 mg/ml.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methylprednisolone Acetate BP 40 mg/ml.

3    PHARMACEUTICAL FORM

Sterile, aqueous suspension.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Depo-Medrone may be used locally or systemically, particularly where oral therapy is not feasible.

Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional or into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see Contraindications and Undesirable effects).

Intramuscular administration:

1. Rheumatic disorders Rheumatoid arthritis

2. Collagen diseases/arteritis

Systemic lupus erythematosus

3. Dermatological diseases

Severe erythema multiforme (Stevens-Johnson syndrome)

4. Allergic states Bronchial asthma

Severe seasonal and perennial allergic rhinitis Drug hypersensitivity reactions Angioneurotic oedema

5.    Gastro-intestinal diseases Ulcerative colitis Crohn's disease

6.    Respiratory diseases

Fulminating or disseminated tuberculosis (with appropriate antituberculous chemotherapy)

Aspiration of gastric contents

7.    Miscellaneous

TB meningitis (with appropriate antituberculous chemotherapy)

Intra-articular administration:

Rheumatoid arthritis

Osteo-arthritis with an inflammatory component

Soft tissue administration (intrabursal, periarticular, into tendon sheath):

Synovitis not associated with infection

Epicondylitis

Tenosynovitis

Plantar fasciitis

Bursitis

Intralesional:

Keloids

Localized lichen planus Localized lichen simplex Granuloma annulare Discoid lupus erythematosus Alopecia areata

4.2 Posology and method of administration

Depo-Medrone should not be mixed with any other suspending agent or solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever suspension and container permit. Depo-Medrone may be used by any of the following routes: intramuscular, intra-articular, periarticular, intrabursal, intralesional and into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see Contra-indications and Undesirable effects).

Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Special warnings and special precautions for use).

Depo-Medrone vials are intended for single dose use only.

Intramuscular - for sustained systemic effect: Allergic conditions (severe seasonal and perennial allergic rhinitis, asthma, drug reactions), 80 - 120 mg (2 - 3 ml).

Dermatological conditions, 40 - 120 mg (1 - 3 ml).

Rheumatic disorders and collagen diseases (rheumatoid arthritis, SLE), 40 -120 mg (1 - 3 ml) per week.

Dosage must be individualized and depends on the condition being treated and its severity.

Note: Depo-Medrone is not intended for the prophylaxis of severe seasonal and perennial allergic rhinitis or other seasonal allergies and should be administered only when symptoms are present.

The frequency of intramuscular injections should be determined by the duration of clinical response.

In the case of seasonal allergic rhinitis a single injection is frequently sufficient. If necessary, however, a second injection may be given after two to three weeks.

On average the effect of a single 2 ml (80 mg) injection may be expected to last approximately two weeks.

Intra-articular: Rheumatoid arthritis, osteo-arthritis. The dose of Depo-Medrone depends upon the size of the joint and the severity of the condition. Repeated injections, if needed, may be given at intervals of one to five or more weeks depending upon the degree of relief obtained from the initial injection. A suggested dosage guide is: large joint (knee, ankle, shoulder), 20 - 80 mg (0.5 - 2 ml); medium joint (elbow, wrist), 10 - 40 mg (0.25 - 1 ml); small joint (metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular), 4 - 10 mg (0.1 - 0.25 ml).

Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 4 - 30 mg (0.1 - 0.75 ml). In most cases, repeat injections are not needed.

Intralesional: Keloids, localised lichen planus, localized lichen simplex, granuloma annulare, alopecia areata, and discoid lupus erythematosus. For administration directly into the lesion for local effect in dermatological conditions, 20 - 60 mg (0.5 - 1.5 ml). For large lesions, the dose may be distributed by repeated local injections of 20 - 40 mg (0.5 - 1 ml). One to four injections are usually employed. Care should be taken to avoid injection of sufficient material to cause blanching, since this may be followed by a small slough.

Peri-articular: Epicondylitis. Infiltrate 4 - 30 mg (0.1 - 0.75 ml) into the affected area.

Into the tendon sheath: Tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 4 - 30 mg (0.1 - 0.75 ml). In recurrent or chronic conditions, repeat injections may be necessary.

Special precautions should be observed when administering Depo-Medrone. Intramuscular injections should be made deeply into the gluteal muscles. The usual technique of aspirating prior to injection should be employed to avoid intravascular administration. Doses recommended for intramuscular injection must not be administered superficially or subcutaneously.

Intra-articular injections should be made using precise, anatomical localisation into the synovial space of the joint involved. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal and hip joints. The spinal joints, unstable joints and those devoid of synovial space are not suitable. Treatment failures are most frequently the result of failure to enter the joint space. Intra-articular injections should be made with care as follows: ensure correct positioning of the needle into the synovial space and aspirate a few drops of joint fluid. The aspirating syringe should then be replaced by another containing Depo-Medrone. To ensure position of the needle, synovial fluid should be aspirated and the injection made. After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.

Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 per cent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis care should be taken to inject Depo-Medrone into the tendon sheath rather than into the substance of the tendon. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.

Children: Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient, than by age or size.

Elderly patients: When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, 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 Special warnings and special precautions for use).

4.3 Contraindications

Depo-medrone is contra-indicated where there is known hypersensitivity to components and in systemic infection unless specific anti-infective therapy is employed.

Due to its potential for neurotoxicity, Depo-Medrone must not be given by the intrathecal route. In addition, as the product is a suspension it must not be given by the intravenous route (see Undesirable effects).

4.4 Special warnings and precautions for use

Warnings and Precautions:

1.    A Patient Information Leaflet is provided in the pack by the manufacturer.

2.    Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Posology and method of administration).

3.    Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

4.    Depo-Medrone vials are intended for single dose use only. Any multidose use of the product may lead to contamination.

5.    Depo-Medrone is not recommended for epidural, intranasal, intraocular, or any other unapproved route of administration. See Undesirable effects section for details of side-effects reported from some non-recommended routes of administration.

6.    Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone.

7.    While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.

8.    Intralesional doses should not be placed too superficially, particularly in easily visible sites in patients with deeply pigmented skins, since there have been rare reports of subcutaneous atrophy and depigmentation.

9.    Systemic absorption of methylprednisolone occurs following intra-articular injection of Depo-Medrone. Systemic as well as local effects can therefore be expected.

10.    Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.

11.    Following a single dose of Depo-Medrone, plasma cortisol levels are reduced and there is evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. This suppression lasts for a variable period of up to 4 weeks. The usual dynamic tests of HPA axis function can be used to diagnose evidence of impaired activity (e.g. Synacthen test).

12.    Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. 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. 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.

13.    Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

14.    Because rare instances of anaphylactic reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.

15.    Corticosteroids 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.

16.    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.

17.    Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

18.    The use of Depo-Medrone 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 antituberculous 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.

19.    Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Undesirable effects).

20.    The following precautions apply for parenteral corticosteroids: Following intra-articular injection, the occurrence of a marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

Local injection of a steroid into a previously infected joint is to be avoided.

Corticosteroids should not be injected into unstable joints.

Sterile technique is necessary to prevent infections or contamination.

The slower rate of absorption by intramuscular administration should be recognised.

Special precautions:

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

1.    Osteoporosis (post-menopausal females are particularly at risk).

2.    Hypertension or congestive heart failure.

3.    Existing or previous history of severe affective disorders (especially previous steroid psychosis).

4.    Diabetes mellitus (or a family history of diabetes).

5.    History of tuberculosis.

6.    Glaucoma (or a family history of glaucoma).

7.    Previous corticosteroid-induced myopathy.

8.    Liver failure or cirrhosis.

9.    Renal insufficiency.

10.    Epilepsy.

Peptic ulceration.

Fresh intestinal anastomoses.

13.    Predisposition to thrombophlebitis.

14.    Abscess or other pyogenic infections.

15.    Ulcerative colitis.

16.    Diverticulitis.

17.    Myasthenia gravis.

18.    Ocular herpes simplex, for fear of corneal perforation.

19.    Hypothyroidism.

20.    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 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects), 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.

Use in Children: Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction with other medicinal products and other forms of interaction

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

2.    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.

3.    Drugs such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance.

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

5.    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.

6.    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.

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

4.6 Fertility, Pregnancy and lactation

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 intrauterine 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. 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.

Lactation

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. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see Special warnings and special precautions for use).

PARENTERAL CORTICOSTEROID THERAPY - Anaphylactic reaction or allergic reactions, hypopigmentation or hyperpigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post injection flare (following intraarticular use), Charcot-like arthropathy, rare instances of blindness associated with intralesional therapy around the face and head.

GASTRO-INTESTINAL - Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of bowel.

Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS -Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Special warnings and special precautions for use).

MUSCULOSKELETAL - Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, aseptic necrosis, muscle weakness.

FLUID AND ELECTROLYTE DISTURBANCE - Sodium and water retention, potassium loss, hypertension, hypokalaemic alkalosis, congestive heart failure in susceptible patients.

DERMATOLOGICAL - Impaired healing, petechiae and ecchymosis, thin fragile skin, skin atrophy, bruising, striae, telangiectasia, acne.

ENDOCRINE/METABOLIC - Suppression of the hypothalamo-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance. Increased appetite.

NEUROPSYCHIATRIC - A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood psychological dependence and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances and cognitive 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 56%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri) has been reported, usually after treatment withdrawal of methylprednisolone.

OPHTHALMIC - Increased intra-ocular pressure, glaucoma, papilloedema, cataracts with possible damage to the optic nerve, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease, exophthalmos.

GENERAL - Leucocytosis, hypersensitivity including anaphylaxis, thromboembolism, nausea, vertigo.

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 Special warnings and special precautions for use).

A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

CERTAIN SIDE-EFFECTS REPORTED WITH SOME NON-RECOMMENDED ROUTES OF ADMINISTRATION.

Intrathecal:    Usual systemic corticoid adverse reactions, headache,

meningismus, meningitis, paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, convulsions.

Extradural: Wound dehiscence, loss of sphincter control.

Intranasal: Permanent/temporary blindness, rhinitis.

Ophthalmic: (Subconjunctival) - Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.

Miscellaneous injection sites - Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.

4.9 Overdose

There is no clinical syndrome of acute overdosage with Depo-Medrone. Following 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 traumatic episode.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Methylprednisolone acetate is a synthetic glucocorticoid. It has greater antiinflammatory potency than prednisolone and less tendency than prednisolone to induce sodium and water retention. An aqueous suspension may be injected directly into joints and soft tissues in the treatment of rheumatoid arthritis, osteoarthritis, bursitis and similar inflammatory conditions. For prolonged systemic effect it may be administered intramuscularly.

5.2    Pharmacokinetic properties

Absorption:

One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Depo-Medrone. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/mL, the average of the individual peak times was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/mL x hrs (Day 1-21).

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:

In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20a-hydroxymethylprednisolone and 20P-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 Interactions with Other Medicinal Products and Other Forms of Interaction.)

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:

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.

No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialysable.

Methylprednisolone acetate is less soluble than methylprednisolone.

5.3 Preclinical safety data

Methylprednisolone

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:

There was no evidence of a potential for genetic and chromosome mutations when tested in limited studies performed in bacteria and mammalian cells.

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential, as the drug is indicated for short-term treatment only. There were no signs indicative of carcinogenic activity in studies conducted to date.

Reproductive toxicity:

Reproductive fertility studies in animals have not been performed to evaluate specifically the potential of impairment of fertility. There is no evidence that corticosteroids impair fertility.

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

Polyethylene glycol, sodium chloride, myristyl-gamma-picolinium chloride and sterile water for injections.

6.2 Incompatibilities

None stated.

6.3 Shelf life

Shelf-life of the medicinal product as packaged for sale: 60 months.

Depo-Medrone should not be mixed with any other fluid. Discard any remaining suspension after use.

6.4 Special precautions for storage

Depo-Medrone should be protected from freezing.

6.5 Nature and contents of container

Type I flint glass vial with a butyl rubber plug and metal seal. Each vial contains 1 ml, 2ml, or 3 ml of Depo-Medrone 40 mg/ml.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00057/0963

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 07/03/1989.

Last renewal date: 05/09/1996.

10 DATE OF REVISION OF THE TEXT

07/06/2016