INFORMATION FOR HEALTH PROFESSIONALS
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Depo-Medrol is a white aqueous sterile suspension containing Methylprednisolone acetate USP 40mg/ml in a 1ml vial.
Methylprednisolone is an anti-inflammatory steroid. Estimates of the relative potencies of methylprednisolone relative to prednisolone range from 1.13 to 2.1 with an average of 1.5. In general the required daily dose of methylprednisolone can be estimated to be two thirds (or 0.7) the required daily dose of prednisolone. While the effect of parenterally administered methylprednisolone acetate is prolonged, it has the same metabolic and anti-inflammatory actions as orally administered medicine.
Cortisol and its synthetic analogues, such as methylprednisolone acetate, exert their action locally by preventing or suppressing the development of local heat, redness, swelling and tenderness by which inflammation is recognized at the gross level of observation. At the microscopic level, such compounds inhibit not only the early phenomena of the inflammatory process (oedema, fibrin deposition, capillary dilation, migration of phagocytes into the inflammed areas and phagocytic activity) but also the later manifestations (capillary proliferation, fibroblast proliferation, deposition of collagen and still later cicatrisation). These compounds inhibit inflammatory response whether the inciting agent is mechanical, chemical or immunological.
Methylprednisolone acetate is hydrolysed to its active form by serum cholinesterases. In man, methylprednisolone forms a weak dissociable bond with albumin and transcortin. Approximately 40 to 90% of the drug is bound. The intracellular activity of glucocorticoids results in a clear difference between plasma half-life and pharmacological half-life. Pharmacological activity persists after measurable plasma levels have disappeared.
The duration of anti-inflammatory activity of glucocorticoids approximately equals the duration of hypothalamic-pituitary-adrenal (HPA) axis suppression.
I.M. injections of 40mg/ml give after approximately 7.3 ± 1 hour (Tmax) methylprednisolone serum peaks of 1.48 ± 0.86 mcg/100 ml (Cmax). The half-life is in this case 69.3 hours. After a single I.M. injection of 40 to 80mg methylprednisolone acetate, duration of HPA axis suppression ranged from 4 to 8 days. An intra-articular injection of 40mg in both knees (total dose: 80mg) gives after 4 to 8 hours methylprednisolone peaks of approximately 21.5 mcg/100 ml. After intra-articular administration methylprednisolone acetate diffuses from the joint into systemic circulation over approximately 7 days, as demonstrated by the duration of the HPA axis suppression and by the serum methylprednisolone values.
Metabolism of methylprednisolone occurs via hepatic routes qualitatively similar to that of cortisol. The major metabolites are 20 beta-hydroxymethylprednisolone and 20 beta-hydroxy-6-alpha-methyl-prednisone. The metabolites are mainly excreted in the urine as glucuronides, sulphates and unconjugated compounds. These conjugation reactions occur principally in the liver and to some extent in the kidney.
When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of Depo-Medrol is indicated as follows:
Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy; mineralocorticoid supplementation is of particular importance).
Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used).
Congenital adrenal hyperplasia.
Hypercalcemia associated with cancer.
Nonsuppurative thyroiditis.
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
Post-traumatic osteoarthritis
Synovitis of osteoarthritis
Rheumatoid arthritis, including juvenile rheumatoid arthritis
(selected cases may require low-dose maintenance therapy)
Acute and subacute bursitis
Epicondylitis
Acute nonspecific tenosynovitis
Acute gouty arthritis
Psoriatic arthritis
Ankylosing spondylitis
During an exacerbation or as maintenance therapy in selected cases of:
Systemic lupus erythematosus
Systemic dermatomyositis (polymyositis)
Acute rheumatic carditis
Pemphigus
Severe erythema multiforme (Stevens-Johnson Syndrome)
Exfoliative dermatitis
Mycosis fungoides
Bullous dermatitis herpetiformis
Severe seborrhoeic dermatitis
Severe psoriasis
Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in:
Bronchial asthma
Contact dermatitis
Atopic dermatitis
Serum sickness
Seasonal or perennial allergic rhinitis
Drug hypersensitivity reactions
Urticarial transfusion reactions
Acute non-infectious laryngeal edema (epinephrine is the drug of first choice)
Severe acute and chronic allergic and inflammatory processes involving the eye, such as:
Herpes zoster ophthalmicus
Iritis, iridocyclitis
Chorioretinitis
Diffuse posterior uveitis
Optic neuritis
Drug hypersensitivity reactions
Anterior segment inflammation
Allergic conjunctivitis
Allergic corneal marginal ulcers
Keratitis
To tide the patient over a critical period of the disease in:
Ulcerative colitis
Regional enteritis
Symptomatic sarcoidosis
Berylliosis
Fulminating or disseminated pulmonary tuberculosis when used concurrently with
appropriate antituberculous chemotherapy
Loeffler's Syndrome not manageable by other means
Aspiration pneumonitis
Acquired (autoimmune) haemolytic anaemia
Secondary thrombocytopenia in adults
Erythroblastopenia (RBC anaemia)
Congenital (erythroid) hypoplastic anaemia
For palliative management of:
Leukemias and lymphomas
Acute leukaemia of childhood
To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uraemia, of the idiopathic type or that due to lupus erythematosus.
Acute exacerbations of multiple sclerosis.
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.
Trichinosis with neurologic or myocardial involvement.
As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
Post-traumatic osteoarthritis
Synovitis of osteoarthritis
Rheumatoid arthritis
Acute and subacute bursitis
Epicondylitis
Acute nonspecific tenosynovitis
Acute gouty arthritis
For intralesional administration
Depo-Medrol is indicated for intralesional use in the following conditions:
Keloids, localised hypertrophic, infiltrated, inflammatory lesions of:
Lichen planus, psoriatic plaques,
Granuloma annular
Lichen Simplex chronicus (neurodermatitis),
Discoid lupus erythematosus,
Necrobiosis lipoidica diabeticorum,
Alopecia areata
Depo-Medrol may also be useful in cystic tumours of an aponeurosis or tendon (ganglia).
Ulcerative colitis.
Because of possible physical incompatibilities, Depo-Medrol sterile aqueous suspension (methylprednisolone acetate) should not be diluted or mixed with other solutions.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Therapy with Depo-Medrol does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.
The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide.
| Size of Joint | Examples | Range of Dosage |
|---|---|---|
| Large | Knees, Ankles, Shoulders | 20-80mg |
| Medium | Elbows, Wrists | 10-40mg |
| Small | Metacarpophalangeal Interphalangeal Sternoclavicular Acromioclavicular |
4-10mg |
PROCEDURE
It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle.
The injection site for each joint is determined by the location where the synovial cavity is most superficial and most free of large vessels and nerves. With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of Depo-Medrol. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing.
Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is occasionally encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area.
Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile. Local therapy does not alter the underlying disease process and, whenever possible, comprehensive therapy including physiotherapy and orthopaedic correction should be employed.
Following intra-articular corticosteroid therapy care should be taken to avoid overuse of joints in which symptomatic 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.
Unstable joints should not be injected. Repeated intra-articular injection may in some cases result in instability of the joint. X-ray follow-up is suggested in selected cases to detect deterioration.
If a local anaesthetic is used prior to injection of Depo-Medrol, the anaesthetic package insert should be read carefully and all the precautions observed.
The area around the injection site is prepared in a sterile way and a wheal at the site made with one percent 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 conditions such as tendinitis or tenosynovitis, care should be taken, following application of a suitable antiseptic to the overlying skin, to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch.
When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases a single injection causes a marked decrease in the size of the cystic tumour and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection.
The dose in the treatment of the various conditions of the tendinous or bursal structures listed above varies with the condition being treated and ranges from 4 to 30mg. In recurrent or chronic conditions, repeated injections may be necessary.
Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 to 60mg of the suspension is injected into the lesion. It may be necessary to distribute doses ranging from 20 to 40mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection.
The intramuscular dosage will vary with the condition being treated. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by seven and given as a singular intramuscular injection.
Dosage must be individualised according to the severity of the disease and response of the patient. For infants and children, the recommended dosage will have to be reduced, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight. Use in children should be limited to the shortest possible time.
Hormone therapy is adjunct to, and not a replacement for, conventional therapy. Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. The severity, prognosis and expected duration of the disease and the reaction of the patient to medication are primary factors in determining dosage. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia.
In patients with the adrenogenital syndrome, a single intra-muscular injection of 40mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 to 120mg. The usual dosage for patients with dermatologic lesions benefited by systemic corticoid therapy is 40 to 120mg of methyl-prednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single dose of 80mg to 120mg. In chronic contact dermatitis repeated at five to ten day intervals may be necessary. In seborrhoeic dermatitis, a weekly dose of 80mg may be adequate to control the condition.
Following intramuscular administration of 80 to 120mg to asthmatic patients, relief may result within six to 48 hours and persist for several days to two weeks. Similarly, in patients with allergic rhinitis (hay fever), an intramuscular dose of 80 to 120mg may be followed by relief of coryzal symptoms within six hours, persisting for several days to three weeks.
If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intra-venous administration of highly soluble methylprednisolone sodium succinate is indicated.
Depo-Medrol sterile aqueous suspension in doses of 40 to 120mg administered as retention enemas or by continuous drip three to seven times weekly for periods of two or more weeks, have been shown to be a useful adjunct in the treatment of some patients with ulcerative colitis. Many patients can be controlled with 40mg of Depo-Medrol sterile aqueous suspension administered in from 30-300ml of water depending upon the degree of involvement of the inflamed colonic mucosa. Other accepted therapeutic measures should, of course, be instituted.
Intrathecal administration.
Systemic fungal infections.
Intravenous administration.
Known hypersensitivity to components.
This product is not suitable for multidose use. Following administration of the desired dose, any remaining suspension should be discarded.
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 minimise 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-synovial 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.
Depo-Medrol should not be administered by any route other than those listed under INDICATIONS. It is critical that, during administration of Depo-Medrol, appropriate technique be used and care taken to assure proper placement of drug.
Administration by other than indicated routes has been associated with reports of serious medical events including: arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, seizures, visual impairment including blindness, ocular and periocular inflammation, and residue or slough at injection site.
In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.
Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location in the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humeral immunity, or neutrophil function. These infections may be mild, but can be severe and at times fatal. With increasing doses of cortico-steroids, the rate of occurrence of infectious complications increases. Caution must therefore be exercised in patients with HIV/AIDS or diabetes. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the response to such vaccines may be diminished. Indicated immunisation procedures may be undertaken in patients receiving non-immunosuppressive doses of corticosteroids.
The use of Depo-Medrol 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 appropriate antituberculosis regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is very important as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
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 allergy to any drug. Allergic skin reactions have been reported apparently related to the excipients in the formulation. Rarely has skin testing demonstrated a reaction to methylprednisolone acetate, per se.
Corticosteroids should not be injected into unstable joints.
Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation.
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.
Corticosteroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection. Caution must also be used in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, oesophagitis, gastritis, renal insufficiency, hypertension, cardiac disease or congestive heart failure, osteoporosis, and myasthenia gravis, when steroids are used as direct or adjunctive therapy.
The following additional precautions apply for parenteral corticosteroids. Intra-synovial injection of a corticosteroid may produce systemic as well as local effects.
Appropriate examination of any joint fluid present is necessary to exclude a septic process.
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.
Sterile technique is necessary to prevent infections or contamination.
The slower rate of absorption by intramuscular administration should be recognised.
Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see Dosage and Administration).
Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause foetal malformations. Adequate human reproductive studies have not been done with corticosteroids. Therefore the use of this drug in pregnancy, nursing mothers, or women of child bearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or foetus. Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy only if clearly needed.
Corticosteroids readily cross the placenta. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency.
There are no known effect of corticosteroids on labour and delivery.
Corticosteroids are excreted in breast milk, therefore the potential benefit of treatment must be weighed against the potential hazards to the infant.
Growth may be suppressed in children receiving longterm daily-divided dose glucocorticoid therapy. The use of such a regimen should be restricted to those most serious indications.
No evidence exists showing that corticosteroids are carcinogenic, mutagenic or impair fertility.
Note the following are typical for all systemic steroids. Their inclusion in this list does not necessarily indicate that the specific event has been observed with this particular formulation.
FLUID AND ELECTROLYTE DISTURBANCES
Sodium retention
Fluid retention
Congestive heart failure in susceptible patients
Potassium loss
Hypokalemic alkalosis
Hypertension
MUSCULOSKELETAL
Muscle weakness
Steroid myopathy
Osteoporosis
Vertebral compression fractures
Aseptic necrosis
Pathologic fractures
Tendon rupture, particularly of the Achilles tendon
GASTROINTESTINAL
Peptic ulcer with possible subsequent perforation and haemorrhage
Gastric haemorrhage
Perforation of the bowel
Pancreatitis
Oesophagitis
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.
DERMATOLOGIC
Impaired wound healing
Thin fragile skin
Petechiae and ecchymoses
NEUROLOGIC
Increased intracranial pressure
Pseudotumor cerebri
Psychic derangements
Seizures
ENDOCRINE
Menstrual irregularities
Development of Cushingoid state
Suppression of growth in children
Suppression of pituitary - adrenal axis
Decreased carbohydrate tolerance
Manifestations of latent diabetes mellitus
Increased requirements for insulin or oral hypoglycemic agents in diabetics
OPHTHALMIC
Posterior subcapsular cataracts
Increased intraocular pressure
Exophthalmos
METABOLIC
Negative nitrogen balance due to protein catabolism.
IMMUNE SYSTEM
Masking of infections
Latent infections becoming active
Opportunistic infections
Hypersensitivity reactions including anaphylaxis
May suppress reactions to skin tests
The following additional reactions are related to parenteral corticosteroid therapy:
The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone, therefore it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of methylprednisolone and may require increase in methylprednisolone dose to achieve the desired response.
Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to a decrease in salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinaemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore coagulation indices should be monitored to maintain the desired anticoagulant effect.
There is no clinical syndrome of acute overdosage with Depo-Medrol (methylprednisolone acetate).
Repeated frequent doses (daily or several times per week) over a protracted period may result in a Cushingoid state.
Store at controlled room temperature 20° to 25°C.
Prescription medicine.
40mg/ml - 1ml vial.
Depo-Medrol is a registered trademark.
Depo-Medrol contains myristy-gamma-picolinium chloride (0.02%) as a preservative.
Pharmacia
PO Box 11-282
Ellerslie
Auckland
New Zealand
Ph: (09) 580 4300
11th December 2001
(Ref: CPS Reviewed 28/6/00)