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Solu-Cortef

Generic Name: hydrocortisone sodium succinate
Dosage Form: For injection, usp

For Intravenous or Intramuscular Administration

Solu-Cortef Description

Solu-Cortef Sterile Powder contains hydrocortisone sodium succinate as the active ingredient. Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in acetone and insoluble in chloroform. The chemical name is pregn-4-ene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)- and its molecular weight is 484.52.

The structural formula is represented below:

Hydrocortisone sodium succinate is an anti-inflammatory adrenocortical steroid. This highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly.

Solu-Cortef Sterile Powder is available in several packages for intravenous or intramuscular administration.

100 mg Plain—Vials containing hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, also 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried.

ACT-O-VIAL® System (Single-Dose Vial) in four strengths:
	100 mg ACT-O-VIAL	250 mg ACT-O-VIAL	500 mg ACT-O-VIAL	1000 mg ACT-O-VIAL
	Each 2 mL contains: (when mixed)	Each 2 mL contains: (when mixed)	Each 4 mL contains: (when mixed)	Each 8 mL contains: (when mixed)
Hydrocortisone sodium succinate	equiv. to 100 mg Hydrocor- tisone	equiv. to 250 mg Hydrocor- tisone	equiv. to 500 mg Hydrocor- tisone	equiv. to 1000 mg Hydrocor- tisone
Monobasic sodium phosphate anhydrous	0.8 mg	2 mg	4 mg	8 mg
Dibasic sodium phosphate dried	8.73 mg	21.8 mg	44 mg	87.32 mg
Benzyl alcohol added as preservative	18.1 mg	16.4 mg	33.4 mg	66.9 mg

When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8.

ACTIONS

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have saltretaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body"s immune response to diverse stimuli.

Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection.

INDICATIONS

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, Solu-Cortef Sterile Powder is indicated for intravenous or intramuscular use in the following conditions:

1.: 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
Hypercalcemia associated with cancer
Nonsuppurative thyroiditis
2.: Rheumatic Disorders
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
3.: Collagen Diseases
During an exacerbation or as maintenance therapy in selected cases of:
Systemic lupus erythematosus
Systemic dermatomyositis (polymyositis)
Acute rheumatic carditis
4.: Dermatologic Diseases
Pemphigus
Severe erythema multiforme (Stevens-Johnson syndrome)
Exfoliative dermatitis
Bullous dermatitis herpetiformis
Severe seborrheic dermatitis
Severe psoriasis
Mycosis fungoides
5.: 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)
6.: 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
7.: Gastrointestinal Diseases
To tide the patient over a critical period of the disease in:
Ulcerative colitis (systemic therapy)
Regional enteritis (systemic therapy)
8.: Respiratory Diseases
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
9.: Hematologic Disorders
Acquired (autoimmune) hemolytic anemia
Idiopathic thrombocytopenic purpura in adults (IV only; IM administration is contraindicated)
Secondary thrombocytopenia in adults
Erythroblastopenia (RBC anemia)
Congenital (erythroid) hypoplastic anemia
10.: Neoplastic Diseases
For palliative management of:
Leukemias and lymphomas in adults
Acute leukemia of childhood
11.: Edematous States
To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
12.: Nervous System
Acute exacerbations of multiple sclerosis
13.: Miscellaneous
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
Trichinosis with neurologic or myocardial involvement

Contraindications

The use of Solu-Cortef Sterile Powder is contraindicated in premature infants because the 100 mg, 250 mg, 500 mg and 1000 mg ACT-O-VIAL System contain benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Solu-Cortef Sterile Powder is also contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.

Warnings

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 localize infection when corticosteroids are used. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location of 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.1

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.2

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.

Usage in pregnancy

Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers, or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

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 the 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 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 nonimmunosuppressive doses of corticosteroids.

The use of Solu-Cortef Sterile Powder 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 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.

Because rare instances of anaphylactoid reactions (eg, 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.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Precautions

General precautions

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.

Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation.

The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction must be gradual.

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 infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, and myasthenia gravis.

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully followed.

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

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).

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, 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.

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.

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 corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin 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 anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

Information for the Patient

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Adverse Reactions

Fluid and Electrolyte Disturbances

: Sodium retention
: Fluid retention
: Congestive heart failure in susceptible patients
: Potassium loss
: Hypokalemic alkalosis
: Hypertension

Musculoskeletal

: Muscle weakness
: Steroid myopathy
: Loss of muscle mass
: Osteoporosis
: Tendon rupture, particularly of the Achilles tendon
: Vertebral compression fractures
: Aseptic necrosis of femoral and humeral heads
: Pathologic fracture of long bones

Gastrointestinal

: Peptic ulcer with possible perforation and hemorrhage
: Pancreatitis
: Abdominal distention
: Ulcerative esophagitis
: 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
: Facial erythema
: Increased sweating
: May suppress reactions to skin tests

Neurological

: Convulsions
: Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment
: Vertigo
: Headache

Endocrine

: Menstrual irregularities
: Development of Cushingoid state
: Suppression of growth in children
: Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness
: Decreased carbohydrate tolerance
: Manifestations of latent diabetes mellitus
: Increased requirements of insulin or oral hypoglycemic agents in diabetics

Ophthalmic

: Posterior subcapsular cataracts
: Increased intraocular pressure
: Glaucoma
: Exophthalmos

Metabolic

: Negative nitrogen balance due to protein catabolism

The following additional reactions are related to parenteral corticosteroid therapy:

: Allergic, anaphylactic or other hypersensitivity reactions
: Hyperpigmentation or hypopigmentation
: Subcutaneous and cutaneous atrophy
: Sterile abscess

Solu-Cortef Dosage and Administration

This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous 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 Solu-Cortef Sterile Powder intravenously over a period of 30 seconds (eg, 100 mg) to 10 minutes (eg, 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 48–72 hours, hypernatremia may occur. Under such circumstances it may be desirable to replace SOLUCORTEF with a corticoid such as methylprednisolone sodium succinate which causes little or no sodium retention.

The initial dose of Solu-Cortef Sterile Powder is 100 mg to 500 mg, 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.

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

Preparation of Solutions

100 mg Plain—For intravenous or intramuscular injection, prepare solution by aseptically adding not more than 2 mL of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial. For intravenous infusion, first prepare solution by adding not more than 2 mL of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 to 1000 mL of the following: 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction).

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.

Further dilution is not necessary for intravenous or intramuscular injection. For intravenous infusion, first prepare solution as just described. The 100 mg solution may then be added to 100 to 1000 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 1000 mL, the 500 mg solution may be added to 500 to 1000 mL and the 1000 mg solution to 1000 mL of the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 3000 mg of SOLUCORTEF 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 IV piggyback.

When reconstituted as directed, pH"s of the solutions range from 7 to 8 and the tonicities are: 100 mg ACT-O-VIAL, .36 osmolar; 250 mg ACT-O-VIAL, 500 mg ACT-O-VIAL, and the 1000 mg ACT-O-VIAL, .57 osmolar. (Isotonic saline=.28 osmolar.)

How is Solu-Cortef Supplied

Solu-Cortef Sterile Powder is available in the following packages:

100 mg Plain—NDC 0009-0825-01
100 mg ACT-O-VIAL (Single-Dose Vial)         250 mg ACT-O-VIAL (Single-Dose Vial)
        2 mL—NDC 0009 - 0900 - 13                  2 mL—NDC 0009-0909-08
25 × 2 mL—NDC 0009-0900-20          25 × 2 mL—NDC 0009-0909-16
500 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0912-05
1000 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0920-03

STORAGE CONDITIONS

Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Store solution at controlled room temperature 20° to 25°C (68° to 77°F) and protect from light. Use solution only if it is clear. Unused solution should be discarded after 3 days.

REFERENCES

1.: Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. Philadelphia: WBSaunders Company 1992:1050–1.
2.: Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 1989:11(6):954–63.

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