Hydrocortone phosphate injection, sterile

Description

Hydrocortisone sodium phosphate, a synthetic adrenocortical steroid, is a white to light yellow, odorless or practically odorless powder. It is freely soluble in water and is exceedingly hygroscopic. The molecular weight is 486.41. It is designated chemically as 11(beta),17-dihydroxy-21-(phosphonooxy)- pregn-4-ene-3,20-dione disodium salt. The empirical formula is C 21 H 29 Na 2 O 8 P and the structural formula is:

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HYDROCORTONE* Phosphate (Hydrocortisone Sodium Phosphate) injection is a sterile solution (pH 7.5 to 8.5), sealed under nitrogen, for intravenous, intramuscular, and subcutaneous administration.

Each milliliter contains hydrocortisone sodium phosphate equivalent to 50 mg hydrocortisone. Inactive ingredients per mL: 8 mg creatinine, 10 mg sodium citrate, sodium hydroxide to adjust pH, and Water for Injection, q.s. 1 mL, with 3.2 mg sodium bisulfite, 1.5 mg methylparaben, and 0.2 mg propylparaben added as preservatives.

*Registered trademark of MERCK & CO., INC.

ACTIONS

HYDROCORTONE Phosphate injection has a rapid onset but short duration of action when compared with less soluble preparations. Because of this, it is suitable for the treatment of acute disorders responsive to adrenocortical steroid therapy.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are also 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 responses to diverse stimuli.

INDICATIONS

When oral therapy is not feasible:

  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
      Nonsuppurative thyroiditis
      Hypercalcemia associated with cancer
  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
      Acute rheumatic carditis
      Systemic dermatomyositis (polymyositis)
  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
      Keratitis
      Allergic corneal marginal ulcers
  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 (I.V. only; I.M. 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. Miscellaneous
      Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
      Trichinosis with neurologic or myocardial involvement

Contraindications

Systemic fungal infections (see WARNINGS regarding amphotericin B)

Hypersensitivity to any component of this product, including sulfites (see WARNINGS )

Warnings

Because rare instances of anaphylactoid 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. Anaphylactoid and hypersensitivity reactions have been reported for Injection HYDROCORTONE Phosphate (see ADVERSE REACTIONS ).

Injection HYDROCORTONE Phosphate contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control life-threatening drug reactions due to amphotericin B. Moreover, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive failure.

In patients on corticosteroid therapy subjected to any unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.

Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and 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. If the patient is receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. (See PRECAUTIONS .)

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. Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results.

In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

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, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible 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.

Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.

Average and large doses of cortisone or 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 virus vaccines, including smallpox, is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained. However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune patients on corticosteroids. In such patients who have not had these diseases, particular care should be taken to avoid exposure. The risk of developing a disseminated infection varies among individuals and can be related to the dose, route and duration of corticosteroid administration as well as to the underlying disease. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. If exposed to measles, prophylaxis with immune globulin (IG) may be indicated. (See the respective package inserts for VZIG and IG for complete prescribing information.)

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.

The use of HYDROCORTONE Phosphate injection in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Precautions

This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial.

Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including fever, myalgia, arthralgia, and malaise. This may occur in patients even without evidence of adrenal insufficiency.

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.

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

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. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism.

When large doses are given, some authorities advise that antacids be administered between meals to help to prevent peptic ulcer.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Phenytoin, phenobarbital, ephedrine, and rifampin may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity, thus requiring adjustment in corticosteroid dosage.

Ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal (see WARNINGS ).

The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time because of reports that corticosteroids have altered the response to these anticoagulants. Studies have shown that the usual effect produced by adding corticosteroids is inhibition of response to coumarins, although there have been some conflicting reports of potentiation not substantiated by studies.

When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should be observed closely for development of hypokalemia.

Injection of a steroid into an infected site is to be avoided.

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

Information for Patients

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

Pediatric Use

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully followed.

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

  Vertebral compression fractures

  Aseptic necrosis of femoral and humeral heads

  Pathologic fracture of long bones

  Tendon rupture

Gastrointestinal

  Peptic ulcer with possible subsequent perforation and hemorrhage

  Perforation of the small and large bowel, particularly in patients with inflammatory bowel disease

  Pancreatitis

  Abdominal distention

  Ulcerative esophagitis

Dermatologic

  Impaired wound healing

  Thin fragile skin

  Petechiae and ecchymoses

  Erythema

  Increased sweating

  May suppress reactions to skin tests

  Burning or tingling, especially in the perineal area (after I.V. injection)

  Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema

Neurologic

  Convulsions

  Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment

  Vertigo

  Headache

  Psychic disturbances

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

  Hyperglycemia

  Increased requirements for insulin or oral hypoglycemic agents in diabetics

  Hirsutism

Ophthalmic

  Posterior subcapsular cataracts

  Increased intraocular pressure

  Glaucoma

  Exophthalmos

Metabolic

  Negative nitrogen balance due to protein catabolism

Cardiovascular

  Myocardial rupture following recent myocardial infarction (see WARNINGS )

Other

  Anaphylactoid or hypersensitivity reactions

  Thromboembolism

  Weight gain

  Increased appetite

  Nausea

  Malaise

The following additional adverse reactions are related to parenteral corticosteroid therapy:

  Rare instances of blindness associated with intralesional therapy around the face and head

  Hyperpigmentation or hypopigmentation

  Subcutaneous and cutaneous atrophy

  Sterile abscess

Overdosage

Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.

The intraperitoneal LD 50 of hydrocortisone in female mice was 1740 mg/kg.

Dosage and Administration

For intravenous, intramuscular, and subcutaneous injection.

For single dose use only. Maintenance of sterility cannot be assured when used as a multiple dose vial.

HYDROCORTONE Phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

Benzyl alcohol as a preservative has been associated with toxicity in premature infants. Solutions used for intravenous administration or further dilution of this product should be preservative-free when used in the neonate, especially the premature infant.

When it is mixed with an infusion solution, sterile precautions should be observed. Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

The initial dosage varies from 15 to 240 mg a day depending on the disease being treated. In less severe diseases doses lower than 15 mg may suffice, while in severe diseases doses higher than 240 mg may be required. Usually the parenteral dosage ranges are one-third to one-half the oral dose given every 12 hours. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

The initial dosage should be maintained or adjusted until the patient's response is satisfactory. If a satisfactory clinical response does not occur after a reasonable period of time, discontinue HYDROCORTONE Phosphate injection and transfer the patient to other therapy.

After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.

If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

How Supplied

No. 7633--Injection HYDROCORTONE Phosphate, 50 mg hydrocortisone equivalent per mL, is a clear, light yellow solution, and is supplied as follows:

NDC 0006-7633-04 in 2 mL single dose vials.

Storage

Sensitive to heat. Do not autoclave.

9024030  Issued November 2001

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