Incidence of Hematoma Complication withHeparin Venous Thrombosis Prophylaxis afterTRAM Flap Breast Reconstruction Background: Randomized controlled studies provide ample evidence that hep- arin is effective in reducing the risk of thromboembolic complications. Never-theless, plastic surgeons are often reluctant to use heparin chemoprophylaxisfor fear of postoperative bleeding. The authors i
Solu-medrol lpd version 2.0SOLU-MEDROL
NAME OF MEDICINAL PRODUCT
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredient: Methylprednisolone sodium succinate Methylprednisolone sodium succinate is available for intravenous or intramuscular administration as: Act-O-Vial System (Single-Dose Vial)
40mg/mL containing methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone.
125mg/2mL containing methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone.
500mg/4mL containing methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone.
1gm/8mL containing methylprednisolone sodium succinate equivalent to 1 gm methylprednisolone.
500mg/8mL vial containing methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone.
1 gm/8mL vial containing methylprednisolone sodium succinate equivalent to 1 gm methylprednisolone.
4.1 Therapeutic Indications
Methylprednisolone sodium succinate is indicated in the following conditions: Endocrine Disorders
Primary or secondary adrenocortical insufficiency (in conjunction with mineralocorticoids, where applicable)Acute adrenocortical insufficiency (mineralocorticoid supplementation may be necessary) Preoperatively, or in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtfulCongenital adrenal hyperplasiaNonsuppurative thyroiditisHypercalcaemia associated with cancer.
Rheumatic Disorders (as adjunctive therapy for short-term administration in the management of an acute
Post-traumatic osteoarthritisSynovitis of osteoarthritisRheumatoid arthritis, including juvenile rheumatoid arthritis Acute and subacute bursitisEpicondylitisAcute nonspecific tenosynovitisAcute gouty arthritisPsoriatic arthritisAnkylosing spondylitis.
Collagen Diseases And Immune Complex Diseases (during an exacerbation or as maintenance therapy in
Systemic lupus erythematosus (and lupus nephritis)Acute rheumatic carditisSystemic dermatomyositis (polymyositis)Polyarteritis nodosaGoodpasture's syndrome.
PemphigusSevere erythema multiforme (Stevens-Johnson syndrome)Exfoliative dermatitisBullous dermatitis herpetiformisSevere seborrheic dermatitisSevere psoriasisMycosis fungoides.
Allergic States (to control severe or incapacitating allergic conditions intractable to adequate trials of
Contact dermatitisAtopic dermatitisSerum sicknessSeasonal or perennial allergic rhinitis Drug hypersensitivity reactions Urticarial transfusion reactions Acute noninfectious laryngeal edema (epinephrine is the drug of first choice).
Ophthalmic Diseases (severe
acute and chronic allergic and inflammatory processes involving the eye) Herpes zoster opthalmicusIritis, iridocyclitisChorioretinitisDiffuse posterior uveitis and choroiditisOptic neuritisSympathetic ophthalmia Anterior segment inflammationAllergic conjunctivitisAllergic corneal marginal ulcersKeratitis.
Gastrointestinal Diseases (to
Ulcerative colitis (systemic therapy)Regional enteritis (systemic therapy).
Symptomatic sarcoidosisBerylliosisFulminating/disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapyLoeffler's syndrome not manageable by other meansAspiration pneumonitis Moderate to severe Pneumocystis carinii pneumonia in AIDS patients (SOLU-MEDROL is beneficial as adjunctive therapy when given within the first 72 hours of initial anti-pneumocystis treatment) Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) Hematological Disorders
Acquired (autoimmune) hemolytic anemiaIdiopathic thrombocytopenic purpura in adults (I.V. only; I.M. administration is contraindicated)Secondary thrombocytopenia in adultsErythroblastopenia (R.B.C. anemia)Congenital (erythroid) hypoplastic anemia. Neoplastic Diseases (palliative management)
Leukemias and lymphomas in adultsAcute leukemia of childhood To improve quality of life in patients with terminal cancer.
To induce diuresis or remission of proteinuria in nephrotic syndrome without uremia.
Cerebral edema from primary or metastatic tumors, or surgical or radiation therapy Acute exacerbations of multiple sclerosis Acute spinal cord injury. The treatment should begin within 8 hours of injury.
Tuberculosis meningitis with subarachnoid block or impending block (when used concurrently with appropriate antituberculous chemotherapy) Trichinosis with neurologic or myocardial involvement Prevention of nausea and vomiting associated with cancer chemotherapy.
4.2 Posology and Method of Administration
Methylprednisolone sodium succinate may be administered by intravenous (I.V.) injection or infusion, or by intramuscular (IM) injection. The preferred method for initial emergency use is I.V. injection. See Table 1 for recommended dosages. Dosage may be reduced for infants and children but should be selected based on the severity of the condition and the response of the patient rather than on the age or weight of the patient. The pediatric dosage should not be less than 0.5 mg/kg every 24 hours.
Table 1. Recommended dosages for methylprednisolone sodium succinate.
Adjunctive therapy in life-threatening conditions Administer 30 mg/kg I.V. over a period of at least 30 minutes. Dose may be repeated every 4 to 6 hours for up to 48 hours.
Rheumatic disorders unresponsive to standard therapy Administer either regimen as I.V. pulse dosing over at least 30 minutes. The regimen may be repeated if improvement has not occurred within a week after therapy, or as the patient's condition dictates.
1 g/day for 1 to 4 days, or
Systemic lupus erythematosus unresponsive to standard Administer 1 g/day for 3 days as I.V. pulse dosing therapy (or during exacerbation episodes) over at least 30 minutes. The regimen may be repeated if improvement has not occurred within a week after therapy, or as the patient's condition dictates.
Multiple sclerosis unresponsive to standard therapy Administer 1 g/day for 3 or 5 days as I.V. pulse dosing over at least 30 minutes. The regimen may be repeated if improvement has not occurred within a week after therapy, or as the patient's condition dictates.
Edematous states, such as glomerulonephritis or lupus Administer either regimen as I.V. pulse dosing over nephritis, unresponsive to standard therapy (or during at least 30 minutes. The regimen may be repeated if improvement has not occurred within 1 week after therapy, or as the patient's condition dictates.
30 mg/kg every other day for 4 days40, or Terminal cancer (to improve quality of life) Administer 125 mg /day I.V. for up to 8 weeks.
Prevention of nausea and vomiting associated with For mild to moderately emetogenic
Administer 250 mg I.V. over at least 5 minutes 1 hour
before start of chemotherapy. Repeat dose of
methylprednisolone at the initiation of chemotherapy
and at the time of discharge. A chlorinated
phenothiazine may also be used with the first dose of
methylprednisolone for increased effect.
For severely emetogenic chemotherapy:
Administer 250 mg I.V. over at least 5 minutes with
appropriate doses of metoclopramide or
abutyrophenone 1 hour before start of chemotherapy. Repeat dose of methylprednisolone at the initiation of chemotherapy and at the time of discharge.
Treatment should begin within 8 hours of injury.
For patients initiated on treatment within 3 hours of injury: Administer 30 mg/kg as an I.V. bolus over a 15-minute period, followed by a 45-minute pause, and then a continuous I.V. infusion of 5.4 mg/kg/h for 23 .
hours. For patients initiated on treatment within 3 to 8 hours of injury: Administer 30 mg/kg as an I.V. bolus over a 15-minute period, followed by a 45-minute pause, and then a continuous I.V. infusion of 5.4 mg/kg/h for 47 hours.
There should be a separate intravenous site for the infusion pump.
Pneumocystis carinii pneumonia in patients with AIDS3,4 Therapy should begin within 72 hours of initial anti-pneumocystis treatment.
One possible regimen is to administer 40 mg I.V. every 6 to 12 hours with gradual tapering over a maximum of 21 days or until the end of pneumocystis therapy.
Due to the increased rate of reactivation of tuberculosis in AIDS patients, consideration should be given to the administration of antimycobacteria therapy if corticosteroids are used in this high risk group.The patient should also be observed for a c t i v a t i o n o f o t h e r l a t e n t i n f e c t i o n s .
Exacerbation of chronic obstructive pulmonary disease 0.5 mg/kg I.V. every 6 hours for 72 hours, or
125 mg I.V. every 6 hours for 72 hours, switch to an oral corticosteroid and taper dose. Total treatment period should be at least 2 weeks.
As adjunctive therapy in other indications Initial dose will vary from 10 to 500 mg I.V., depending on the clinical condition. Larger doses may be required for short-term management of severe, acute conditions. Initial doses up to 250 mg should be administered I.V. over a period of at least 5 minutes, while larger doses should be administered over at least 30 minutes. Subsequent doses may be administered I.V. or I.M. at intervals dictated by the patient's response and clinical condition.Initial doses up to 250 mg should be administered I.V. over a period of at least 5 minutes, while larger doses s h o u l d b eadministered over at least 30 minutes. S u b s e q u e n t doses may be administered I.V. or I.M. at intervals dictated by the patient's response and clinical condition. To avoid compatibility and stability problems, it is recommended that methylprednisolone sodium succinate be
administered separately from other drugs whenever possible, as either I.V. push, through an I.V. medication
chamber, or as an I.V. "piggy-back" solution (See section 6.6 Instructions for Use/Handling).
Methylprednisolone sodium succinate is contraindicated in patients who haveSystemic fungal infectionsKnown hypersensitivity to methylprednisolone or any component of the formulation.
4.4 Special Warnings and Special Precautions for Use
Methylprednisolone sodium succinate should not be used routinely to treat head injury as demonstrated by the results of a multicenter study. The study results revealed an increased mortality in the 2 weeks after injury in patients administered methylprednisolone sodium succinate compared to placebo (1.18 relative risk). A causal association with methylprednisolone sodium succinate treatment has not been established.
Some studies do not establish the efficacy of methylprednisolone sodium succinate in septic shock, and suggest that increased mortality may occur in some subgroups at higher risk (i.e., patients with secondary infections or creatinine In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.
Immunosuppressant Effects/Increased Susceptibility to Infections
Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic organisms, 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 or humoral immunity, or neutrophil function . These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications 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 immunization procedures may be undertaken in patients receiving non-immunosuppressive doses of corticosteroids.
The use of methylprednisolone sodium succinate 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 anti-tuberculosis 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.
Immune System Effects
Because rare instances of anaphylactoid (e.g., bronchospasm) 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.
There are reports of cardiac arrhythmias, and/or circulatory collapse, and/or cardiac arrest following the rapid administration of large intravenous doses of methylprednisolone sodium succinate (more than 0.5 g 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 or duration of infusion.
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
Nervous System Effects
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 patients with nonspecific ulcerative colitis if there is a probability of impending perforation, abscess, or other pyogenic infection. Corticosteroids should also be used with caution in patients with diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, or myasthenia gravis.
An acute myopathy has been reported with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
Other Adverse Events
Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
4.5 Interactions with Other Medicaments and Other Forms of Interaction
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 increases in methylprednisolone dose to achieve the desired response.
CYP3A4 inhibitors (such as macrolides, triazole antifungals , and some calcium channel blockers) 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 decreased salicylate serum levels or an increase in the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia.
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.
4.6 Pregnancy and Lactation
Animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations. However, corticosteroids do not appear to cause congenital anomalies when given to pregnant One retrospective study found an increased incidence of low-birth weights in infants born of mothers receiving corticosteroids. Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, methylprednisolone sodium succinate should be used during pregnancy only if clearly needed.
Corticosteroids readily cross the placenta. Although neonatal adrenal insufficiency appears to be rare in infants who were exposed in utero to corticosteroids , those exposed to substantial doses of corticosteroids must be carefully observed and evaluated for signs of adrenal insufficiency. There are no known effects of corticosteroids on labor and delivery. Lactation
Corticosteroids, including prednisolone, are excreted in breast milk.
4.7 Effects on Ability to Drive and Use Machines
The effect of methylprednisolone sodium succinate on the ability to drive or use machinery has not been systematically evaluated.
4.8 Undesirable Effects
NOTE: the following are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily
indicate that the specific event has been observed with this particular formulation.
of infections, latent infections becoming active, opportunistic infections.
Immune System Disorders: hypersensitivity reactions, including anaphylaxis with or without circulatory
collapse, cardiac arrest, bronchospasm.
Endocrine Disorders: development of Cushingoid state, suppression of pituitary-adrenal axis.
Metabolism and Nutrition Disorders: sodium retention, fluid retention, hypokalemic alkalosis, decreased
carbohydrate tolerance, manifestation of latent diabetes mellitus, increased requirements for insulin or oral
hypoglycemic agents in diabetics.
Nervous System Disorders: increased intracranial pressure with papilloedema (pseudotumor cerebri),
Eye Disorders: posterior subcapsular cataracts, exophthalmos.
Cardiac Disorders: congestive heart failure in susceptible patients, myocardial rupture following a myocardial
Vascular Disorders: Hypertension, hypotension, petechiae.
Respiratory, Thoracic and Mediastinal Disorders: persistent hiccups with high doses of corticosteroids.
Gastrointestinal Disorders: peptic ulceration with possible perforation and hemorrhage, gastric hemorrhage,
pancreatitis, esophagitis, perforation of the bowel.
Skin and Subcutaneous Tissue Disorders: ecchymosis, thin fragile skin.
Musculoskeletal and Connective Tissue Disorders: steroid myopathy, muscle weakness, osteoporosis,
Reproductive System and Breast Disorders: menstrual irregularities.
General Disorders and Administration Site Conditions: impaired wound healing, suppression of growth in
Investigations: potassium loss, increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST,
SGOT) and alkaline phosphatase, negative nitrogen balance due to protein catabolism, increased intraocular
pressure, suppression of reactions to skin tests.
Injury, Poisoning and Procedural Complications: pathologic fractures, vertebral compression fractures, tendon rupture, particularly of the Achilles tendon.
There is no clinical syndrome of acute overdosage with methylprednisolone sodium succinate. Methylprednisolone is dialyzable.
5.1 Pharmacodynamic Properties
Methylprednisolone is a potent anti-inflammatory steroid with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention.
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.
5.2 Pharmacokinetic Properties
Methylprednisolone plasma concentrations were measured by an HPLC assay. After a 40 mg intramuscular dose of Methylprednisolone sodium succinate to fourteen healthy adult male volunteers, the average peak concentration of 454 ng/mL was achieved at 1 hour. At 12 hours, the methylprednisolone plasma concentration has declined to 31.9 ng/mL. No methylprednisolone was detected 18 hours after dosing. Based on area-under-the-time-concentration curve, an indication of total drug absorbed, intramuscular methylprednisolone sodium succinate was found to be equivalent to the same dose administered intravenously. Results of a study demonstrated that the sodium succinate ester of methylprednisolone is rapidly and extensively converted to the active methylprednisolone moiety after all routes of administration. Extent of absorption of free methylprednisolone following I.V. and I.M. administrations were found to be equivalent and significantly greater than those following administration of the oral solution and oral methylprednisolone tablets. Since the extent of methylprednisolone absorbed following the I.V. and I.M. treatment was equivalent in spite of the greater amount of the hemisuccinate ester reaching the general circulation after I.V. administration, it appears that the ester is converted in the tissue after I.M. injection with subsequent absorption as free methylprednisolone.
6.1 List of Excipients
Act-O-Vial System (Single-Dose Vial)
40mg/ml: monobasic sodium phosphate dried, lactose, sodium hydroxide, water for injection, benzyl alcohol.
125mg/2ml: monobasic sodium phosphate dried, lactose, sodium hydroxide, water for injection, benzyl
500mg/4ml: monobasic sodium phosphate anhydrous, dibasic sodium phosphate dried, water for injection,
1gm/16ml: monobasic sodium phosphate anhydrous, dibasic sodium phosphate dried, water for injection,
500mg/8ml vial: sodium biphosphate, dried sodium phosphate, water for injection, benzyl alcohol.
1g/16ml: sodium biphosphate, dried sodium phosphate, water for injection, benzyl alcohol.
The I.V. compatibility and stability of methylprednisolone sodium succinate solutions and with other drugs in intravenous admixtures are dependent on admixtures pH, concentration, time, temperature and the ability of methylprednisolone to solubilize itself. Thus, to avoid compatibility and stability problems, whenever possible it is recommended that SOLU-MEDROL Sterile Powder be administered separately from other drugs and as either I.V. push, through and I.V. medication chamber or as an I.V. “piggy-back” solution.
6.3 Shelf Life
6.4 Special Precautions for Storage
Store unreconstituted product at controlled room temperature 15-30 C (59-86 F). Store solution at controlled room temperature 15-30 C (59-86 F). Use solution within 48 hours after mixing.
6.5 Nature and Contents of Container
6.6 Instructions for Use/Handling
Preparation of Solutions
To prepare solutions for intravenous infusion, first reconstitute methylprednisolone sodium succinate as directed. Therapy may be initiated by administering methylprednisolone sodium succinate intravenously over a period of at least five minutes (e.g., doses up to 250 mg) to at least 30 minutes (e.g., doses of 250 mg or more). Subsequent doses may be withdrawn and administered similarly. If desired, the medication may be administered in dilute solutions by admixing the reconstituted product with Dextrose 5% in Water, Normal Saline, Dextrose 5% in 0.45% or 0.9% Sodium Chloride; the resulting solutions are physically and chemically stable for 48 hours.
Directions for using Act-O-Vial Two-Compartment Vial
1. Remove protective cap, give the plunger-stopper a quarter turn and press to force diluent into the lower
2. Gently agitate to effect solution. Use solution within 48 hours.
3. Sterilize top of plunger-stopper with a suitable germicide.
4. Insert needle through center of plunger-stopper until tip is just visible. Invert vial and withdraw dose.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Food and Drug Administration Approved, USA.
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