Solu-Cortef (Hydrocortisone Sodium)

SOLU-CORTEF®

Pharmacia & Upjohn

Hydrocortisone Sodium

Succinate Glucocorticoid

Action and Clinical

Sterile Solu-Cortef–the highly water-soluble sodium succinate ester of hydrocortisone-permits the immediate i.v. administration of high doses of hydrocortisone in a small volume of diluent and is, therefore, particularly useful in situations where high blood levels of hydrocortisone are required rapidly.

Solu-Cortef has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the 2 compounds are equivalent in biologic activity. Following the i.v. injection of hydrocortisone sodium succinate, experimental evidence of its effects has been noted within a few minutes and persists for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, hydrocortisone sodium succinate should be injected every 4 to 6 hours. Hydrocortisone sodium succinate may also be administered by i.v. infusion, or by i.m. injection. The preferred method for initial emergency use is i.v. injection.

Indications And Clinical Uses:

Endocrine Disorders: 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).

Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful. Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected.

Congenital adrenal hyperplasia.

Nonsuppurative thyroiditis.

Hypercalcemia associated with cancer.

Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: post-traumatic osteoarthritis, synovitis or 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.

Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, acute rheumatic carditis, systemic dermatomyositis (polymyositis).

Dermatologic Diseases: pemphigus, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, bullous dermatitis herpetiformis, severe seborrheic dermatitis, severe psoriasis, mycosis fungoides.

Allergic States: 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 noninfectious laryngeal edema (epinephrine is the drug of first choice).
skin.
Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye, such as: herpes zoster ophthalmicus, iritis, iridocyclitis, chorioretinitis, diffuse posterior uveitis and choroiditis, optic neuritis, sympathetic ophthalmia, anterior segment inflammation, allergic conjunctivitis, allergic corneal marginal ulcers, keratitis.

Gastrointestinal Diseases: To tide the patient over a critical period of the disease in: ulcerative colitis (systemic therapy), regional enteritis (systemic therapy).

Respiratory Diseases: symptomatic sarcoidosis, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, Löffler’s syndrome not manageable by other means, aspiration pneumonitis.

Hematologic Disorders: acquired (autoimmune) hemolytic anemia, idiopathic thrombocytopenia purpura in adults (i.v. only; i.m. administration is contraindicated), erythroblastopenia (RBC anemia), congenial (erythoid) hypoplastic anemia, secondary thrombocytopenia in adults.

Neoplastic Diseases: for palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.

Edematous States: To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, or the idiopathic type or that due to lupus erythematosus.

Medical Emergencies: Hydrocortisone is indicated in the treatment of 1) shock secondary to adrenocortical insufficiency or shock unresponsive to conventional therapy when adrenal cortical insufficiency may be present; and 2) acute allergic disorders (status asthmaticus, anaphylactic reactions, insect stings, etc.) following epinephrine.

Although there are no well-controlled (double-blind, placebo) clinical trials, data from experimental animal models indicate that corticosteroids may be useful in hemorrhagic, traumatic and surgical shock in which standard therapy (e.g., fluid replacement, etc.) has not been effective. Also see warning statement.

Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Trichinosis with neurologic or myocardial involvement.

Contra-Indications:

In patients with known hypersensitivity to any components of the product and in patients with systemic fungal infections.

Warnings in Clinical States:

In patients on corticosteroid therapy subjected to unusual stress, increased dosage or 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 localize 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, 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 increases.

Average and large doses of hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Administration of live or live, attenuated vaccines is contra-indicated 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 nonimmunosuppressive doses of corticosteroids.

The use of hydrocortisone 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 necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Because rare instances of anaphylactoid reactions (e.g., bronchospasm) 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.

This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal Gasping Syndrome in premature infants.

Although recent studies have not been conducted with hydrocortisone or other corticosteroids, studies of methylprednisolone sodium succinate in septic shock suggest that increased mortality may occur in some subgroups of patients at higher risk (i.e., elevated creatinine greater than 2.0 mg or with secondary infections).

Pregnancy and Lactation: Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations. Adequate human reproductive studies have not been done with corticosteroids. Therefore the use of this drug in pregnancy, nursing mothers, or women of childbearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or fetus. 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 effects of corticosteroids on labor and delivery. Corticosteroids are excreted in breast milk.

Precautions:

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.

Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infections, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, and myasthenia gravis.

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).

An acute myopathy has been described 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.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There is no evidence that corticosteroids are carcinogenic, mutagenic or impair fertility.

Labor and Delivery: No effect known.

Lactation: Because prednisone is excreted in breast milk, it is reasonable to assume that all corticoids are. No data is known for hydrocortisone sodium succinate.

Children: Growth may be supressed in children receiving long-term, daily-divided dose glucocorticoid therapy. The use of such a regimen should be restricted to the most serious indications.

Drug Interactions:

The pharmacokinetic interactions listed below are potentially clinically important.

Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response.

Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore the dose of corticosteroids should be titrated to avoid steroid toxicity.

Corticosteroids may increase the clearance of chronic high dose ASA. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. ASA should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia.

The effect of corticosteroids 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.

Adverse Reactions:

: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.

Fluid and Electrolyte Disturbances: congestive heart failure in susceptible patients, hypertension, hypokalemic alkalosis. Sodium retention, fluid retention and potassium loss which are correctable and largely preventable by restricting sodium intake to 500 mg/day and supplementing potassium intake.

Musculoskeletal: steroid myopathy, muscle weakness, osteoporosis, pathologic fractures, vertebral compression fractures, aseptic necrosis, loss of muscle mass, tendon rupture–particularly of the Achilles tendon.

Gastrointestinal: peptic ulceration with possible perforation and hemorrhage, gastric hemorrhage, pancreatitis, esophagitis, ulcerative esophagitis, perforation of the bowel, abdominal distention.

Increases in ALT, AST 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 (usually at high doses), petechiae and ecchymoses, thin fragile skin, facial erythema, increased sweating.

Metabolic: negative nitrogen balance due to protein catabolism.

Neurological: increased intracranial pressure, pseudotumor cerebri, psychic derangements, seizures, headache, vertigo.

Endocrine: menstrual irregularities, development of Cushingoid state, suppression of pituitary-adrenal axis leading to secondary adrenocortical and pituitary unresponsiveness, decreased carbohydrate tolerance, manifestation of latent diabetes mellitus, increased requirement for insulin or oral hypoglycemic agents in diabetics, suppression of growth in children.

Ophthalmic: posterior subcapsular cataracts (associated with prolonged, high dose systemic therapy), glaucoma, increased intraocular pressure, exophthalmos.

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: hyperpigmentation or hypopigmentation, s.c. and cutaneous atrophy, sterile abscess, anaphylactoid reaction (e.g., bronchospasm, laryngeal edema, urticaria).

Symptoms And Treatment Of Overdose:

There is no clinical syndrome of acute overdosage with hydrocortisone. Hydrocortisone is dialyzable.

Dosage And Administration:

This preparation may be administered by i.v. injection, by i.v. infusion, or by i.m. injection; the preferred method for initial emergency use being i.v. injection. Following the initial emergency period, consideration should be given to employing a longer-acting injectable preparation or an oral preparation.

Therapy is initiated by administering hydrocortisone sodium succinate i.v. over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In general, high-dose corticosteroid therapy should be continued only until the patient’s condition has stabilized–usually not beyond 48 to 72 hours. Although adverse effects associated with high dose, short-term corticoid therapy are uncommon, peptic ulceration may occur. Prophylactic antacid therapy may be indicated. When high-dose hydrocortisone therapy must be continued beyond 48 to 72 hours, hypernatremia may occur. Under such circumstances it may be desirable to replace hydrocortisone with a corticosteroid product such as methylprednisolone sodium succinate which causes little or no sodium retention.

The initial dose of hydrocortisone is 100 to 500 mg or more depending on the severity of the condition. This dose may be repeated at intervals of 2, 4, or 6 hours as indicated by the patient’s response and clinical condition. While the dose may be reduced for infants and children, it is governed more by the severity of the condition and response of the patient than by age or body weight but should not be less than 25 mg daily.

Patients subjected to severe stress following corticosteroid therapy should be observed closely for signs and symptoms of adrenocortical insufficiency.

Corticosteroid therapy is an adjunct to, and not a replacement for, conventional therapy.

Preparation of Solutions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

I.V./I.M. Injection: To use Solu-Cortef Act-O-Vial reconstitute Act-O-Vial according to Directions For Using The Act-O-Vial System. Further dilution is not necessary for i.v. or i.m. injection.

I.V. Infusion: For i.v. infusion first reconstitute Act-O-Vials according to instructions. The 100 mg solution may then be added to 100 to 1 000 mL of 5% Dextrose in Water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). The 250 mg solution may be added to 250 to 1 000 mL, the 500 mg solution may be added to 500 to 1 000 mL and the 1 000 mg solution to 1 000 mL of the same diluents. In cases, where administration of a small volume of fluid is desirable, 100 mg to 3 000 mg of Solu-Cortef may be added to 50 mL of the above diluents. The resulting solutions are stable for at least 4 hours and may be administered either directly or by i.v. piggy back.

Freezing: In-house studies have shown reconstituted hydrocortisone 50 mg/mL and 125 mg/mL to be physically and chemically stable after 1 month of freezing. Once thawed, the above guidelines should be followed for hydrocortisone.

Directions for Using the Act-O-Vial System: Press down on plastic activator to force diluent into the lower compartment. Gently agitate to effect solution. Remove plastic tab covering center of stopper. Sterilize top of stopper with a suitable germicide. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose.

Storage: Store unreconstituted product at controlled room temperature 15 to 30°C. Store solution at controlled room temperature 15 to 30°C and protect from light. Use solution only if it is clear. Discard unused solutions affter 3 days. The Act-O-Vial is a single dose vial and once reconstituted solution is used, any remaining portion should be discarded.

Availability And Storage:

Act-O-Vials: 100 mg: Each 2 mL (when mixed) contains: hydrocortisone (as hydrocortisone sodium succinate) 100 mg, monobasic sodium phosphate anhydrous 0.8 mg, dibasic sodium phosphate dried 8.76 mg and benzyl alcohol 18.1 mg. Sodium: <1 mmol. Vial packs of 5.

250 mg: Each 2 mL (when mixed) contains: hydrocortisone (as hydrocortisone sodium succinate) 250 mg, monobasic sodium phosphate anhydrous 2 mg, dibasic sodium phosphate dried 21.8 mg and benzyl alcohol 16.4 mg. Sodium: <1 mmol. Vial packs of 5.

500 mg: Each 4 mL (when mixed) contains: hydrocortisone (as hydrocortisone sodium succinate) 500 mg, monobasic sodium phosphate anhydrous 4 mg, dibasic sodium phosphate dried 44 mg and benzyl alcohol 33.4 mg. Sodium: <1 mmol. Vial packs of 5.

1 g: Each 8 mL (when mixed) contains: hydrocortisone (as hydrocortisone sodium succinate) 1 g, monobasic sodium phosphate anhydrous 8 mg, dibasic sodium phosphate dried 87.32 mg and benzyl alcohol 66.9 mg. Sodium: <1 mmol. Vial packs of 5.

SOLU-CORTEF® Pharmacia & Upjohn Hydrocortisone Sodium Succinate Glucocorticoid

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