Cortef Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

Part 1: Healthcare Professional Information........................................................................... 5

1 Indications .................................................................................................................. 5

1.1 Pediatrics......................................................................................................... 6

1.2 Geriatrics ......................................................................................................... 6

2 Contraindications ....................................................................................................... 6

4 Dosage and Administration ........................................................................................ 6

4.1 Dosing Considerations...................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ................................................... 7

4.5 Missed Dose .................................................................................................... 7

5 Overdose .................................................................................................................... 7

6 Dosage Forms, Strengths, Composition and Packaging................................................ 7

7 Warnings and Precautions .......................................................................................... 8

General....................................................................................................................... 8

Carcinogenesis and Genotoxicity ................................................................................ 8

Cardiovascular ............................................................................................................ 8

Driving and Operating Machinery ............................................................................... 9

Endocrine and Metabolism ......................................................................................... 9

Gastrointestinal ........................................................................................................ 10

Hematologic ............................................................................................................. 10

Hepatic/Biliary/Pancreatic........................................................................................ 10

Immune .................................................................................................................... 10

Monitoring and Laboratory Tests .............................................................................. 12

Musculoskeletal........................................................................................................ 12

Neurologic ................................................................................................................ 13

Ophthalmologic ........................................................................................................ 13

Psychiatric ................................................................................................................ 13

Renal ........................................................................................................................ 14

Other ........................................................................................................................ 14

Reproductive Health ................................................................................................. 14

Sensitivity/Resistance............................................................................................... 14

7.1 Special Populations ........................................................................................ 14

7.1.1 Pregnancy .................................................................................................. 14

7.1.2 Breastfeeding............................................................................................. 15

7.1.3 Pediatrics ................................................................................................... 15

7.1.4 Geriatrics ................................................................................................... 16

8 Adverse Reactions .................................................................................................... 16

8.1 Adverse Reaction Overview ............................................................................ 16

9 Drug Interactions ...................................................................................................... 20

9.2 Drug Interactions Overview ............................................................................ 20

9.4 Drug-Drug Interactions................................................................................... 20

9.5 Drug-Food Interactions .................................................................................. 23

9.6 Drug-Herb Interactions................................................................................... 23

9.7 Drug-Laboratory Test Interactions .................................................................. 23

10 Clinical Pharmacology ............................................................................................... 23

10.2 Pharmacodynamics ........................................................................................ 23

10.3 Pharmacokinetics........................................................................................... 24

11 Storage, Stability and Disposal.................................................................................. 25

12 Special Handling Instructions .................................................................................... 25

Part 2: Scientific Information ............................................................................................... 26

13 Pharmaceutical Information ..................................................................................... 26

14 Clinical Trials............................................................................................................. 26

15 Microbiology ............................................................................................................ 26

16 Non-Clinical Toxicology............................................................................................. 26

Patient Medication Information........................................................................................... 28

Part 1: Healthcare Professional Information

1 Indications

CORTEF (hydrocortisone) is indicated for:

• Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance); 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: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, posttraumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis.
• 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, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens Johnson syndrome), exfoliative dermatitis, mycosis fungoides, severe psoriasis and severe seborrheic dermatitis.
• Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness and drug hypersensitivity reactions.
• Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic conjunctivitis, keratitis, allergic corneal marginal ulcers, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, anterior segment inflammation, diffuse posterior uveitis and choroiditis, optic neuritis, sympathetic ophthalmia.
• Respiratory Diseases: Symptomatic sarcoidosis, Löffler's syndrome not manageable by other means, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, aspiration pneumonitis.
• Hematologic Disorders: Idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia), congenital (erythroid) hypoplastic anemia.
• Neoplastic Diseases: For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.
• Edematous States: To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.
• Gastrointestinal Diseases: To tide the patient over a critical period of the disease in ulcerative colitis, regional enteritis.
• Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy, trichinosis with neurologic or myocardial involvement.

1.1 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of CORTEF in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use. See 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics.

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 7 WARNINGS AND PRECAUTIONS, 7.1.4 Geriatrics.

2 Contraindications

• CORTEF (hydrocortisone) is contraindicated in systemic fungal infections. See 7 WARNINGS AND PRECAUTIONS and 9.4 Drug-Drug Interactions.
• CORTEF (hydrocortisone) is contraindicated in patients who are hypersensitive to hydrocortisone or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING and 7 WARNINGS AND PRECAUTIONS.
• CORTEF (hydrocortisone) is contraindicated in patients administered with live or live, attenuated vaccines while receiving immunosuppressive doses of corticosteroids. See 7 WARNINGS AND PRECAUTIONS and 9.4 Drug-Drug Interactions.
• CORTEF (hydrocortisone) is contraindicated in herpes simplex of the eye, except when used for short-term or emergency therapy as in acute sensitivity reactions.
• CORTEF (hydrocortisone) is contraindicated in patients with vaccinia and varicella, except when used for short-term or emergency therapy as in acute sensitivity reactions. See 7 WARNINGS AND PRECAUTIONS and 9.4 Drug-Drug Interactions.

4 Dosage and Administration

4.1 Dosing Considerations

• After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of hydrocortisone tablets for a

  • period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually. See 7 WARNINGS AND PRECAUTIONS.

4.2 Recommended Dose and Dosage Adjustment

The initial dosage of hydrocortisone tablets may vary from 20 to 240 mg of hydrocortisone per day depending on the specific disease entity being treated. It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment, its severity, and the response of the patient over the entire duration of treatment. A risk/benefit decision must be made in each individual case on an ongoing basis. In situations of less severity lower doses for the minimum period will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, hydrocortisone tablets should be discontinued and the patient transferred to another appropriate therapy.

4.5 Missed Dose

Missed dose should be taken as soon as possible. However, if it is almost time for the next dose, your regular dosing schedule should be maintained. Doubling a dose to make up for a missed one is not recommended.

5 Overdose

Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

Hydrocortisone is dialyzable.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition and Packaging

Table – Dosage Forms, Strengths, and Composition

10 mg: Each white, round, scored, compressed tablet, engraved “CORTEF 10”,

20 mg: Each white, round, compressed tablet, engraved “CORTEF 20”

7 Warnings and Precautions

General

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

Patients should be advised to inform subsequent health professionals of the prior use of corticosteroids.

The existence of diabetes, osteoporosis, renal insufficiency, chronic psychosis, hypertension, myasthenia gravis or predisposition to thrombophlebitis requires that CORTEF (hydrocortisone) be administered with caution.

Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids. See 9.4 Drug-Drug Interactions.

Carcinogenesis and Genotoxicity

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

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.

Cardiovascular

Average and large doses of hydrocortisone or cortisone 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.

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, corticosteroids should be used with caution in patients with hypertension and only if strictly necessary, in cases of congestive heart failure.

Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects, if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed. Low dose therapy may reduce the incidence of complications in corticosteroid therapy.

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.

Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result, corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.

Driving and Operating Machinery

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Undesirable effects, such as dizziness, vertigo, visual disturbances and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.

Endocrine and Metabolism

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

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids, including hydrocortisone. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Patients should be monitored for Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome and hyperglycemia with chronic use. Corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticoid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. Pharmacologic doses of corticosteroids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) axis suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration, and duration of glucocorticoid therapy.

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. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly. A steroid “withdrawal syndrome,” seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of glucocorticoids. This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels. Drug-induced adrenocortical insufficiency may be minimized by gradual reduction of dosage.

Because glucocorticoids can produce or aggravate Cushing’s syndrome, glucocorticoids should be avoided in patients with Cushing’s disease.

Corticosteroids, including hydrocortisone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis when steroids are used as direct or adjunctive therapy, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis.

In combination with nonsteroidal anti-inflammatory drugs (NSAIDs), such as Aspirin (acetylsalicylic acid), the risk of developing gastrointestinal ulcers is increased.

Hematologic

Acetylsalicylic acid and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinemia. See 9.4 Drug-Drug Interactions.

Hepatic/Biliary/Pancreatic

Hydrocortisone may have an increased effect in patients with liver disease since the metabolism and elimination of hydrocortisone is significantly decreased in these patients. There is an enhanced effect of corticosteroids in patients with cirrhosis. Hepatobiliary disorders have been reported which may be reversible after discontinuation of therapy. Therefore appropriate monitoring is required.

High doses of corticosteroids may produce acute pancreatitis.

Immune

Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. Corticosteroids may increase susceptibility to infection, may mask some signs of infection, exacerbate existing infections, increase the risk of reactivation or exacerbation of latent infections 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.

Monitor for the development of infection and consider withdrawal of corticosteroids or dosage reduction as needed.

Special pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma. It is recommended that amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Host defenses are impaired in patients receiving large doses of glucocorticoids and this effect increases susceptibility to fungus infections as well as bacterial and viral infections.

Fungal infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. See 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions.

Viral infections

Chickenpox and measles, for example, can have a more serious or even fatal course in nonimmune 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 affect 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 chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.m. immunoglobulin (IG) may be indicated. If chickenpox 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.

Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition.

The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended. A systematic review of short-course, high dose corticosteroids did not support their use. However, meta-analyses, and a review suggest that longer courses (511 days) of low dose corticosteroids might reduce mortality, especially in patients with vasopressor dependent septic shock.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids (see 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions). Killed or inactivated vaccines may be administered however the response to such vaccines may be diminished. Indicated immunization procedures may be undertaken in patients receiving non immunosuppressive doses of corticosteroids.

While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially in high doses, because of possible hazards of neurological complications and lack of antibody response.

Tuberculosis

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 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.

Monitoring and Laboratory Tests

Corticosteroids may suppress reactions to skin tests.

Dosage adjustments may be required based on the following conditions: during remission or exacerbation of the disease process; the patient’s individual response to therapy; or upon exposure of the patient to emotional or physical stress such as serious infection, surgery or injury.

Monitoring for signs and symptoms of drug-induced secondary adrenocortical insufficiency may be necessary for up to one year following cessation of long-term or high-dose corticosteroid therapy.

Musculoskeletal

An acute myopathy has been observed 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. Cases of rhabdomyolysis have been reported. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Osteoporosis is an adverse effect generally associated with long-term use and large doses of corticosteroids at any age. Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age.

Corticosteroids should be used with caution in patients with osteoporosis and in patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy.

Corticosteroids should be used with caution in patients with myasthenia gravis.

Neurologic

Corticosteroids should be used with caution in patients with seizure disorders.

Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

Systemic corticosteroids, including CORTEF, are not indicated for, and therefore should not be used for the treatment of traumatic brain injury, as demonstrated by the results of a multicenter study. The study results revealed an increased mortality in the 2 weeks and 6 months after injury in patients administered methylprednisolone sodium succinate compared to placebo.

There have been reports of epidural lipomatosis in patients taking corticosteroids (including cases in children), typically with long-term use at high doses.

Ophthalmologic

Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. As intraocular pressure may become elevated in some individuals, if steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex except when used for short-term or emergency therapy as in acute sensitivity reactions. Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.

Psychiatric

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.

Potentially severe psychiatric adverse reactions may occur with systemic steroids (see 8 ADVERSE REACTIONS). Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Psychological effects have been reported upon withdrawal of corticosteroids; the frequency is unknown. Patients/caregivers should be encouraged to seek medical attention if psychological symptoms develop in the patient, especially if depressed mood or suicidal ideation is suspected. Patients/caregivers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids.

Renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, corticosteroids should be used with caution in patients with renal insufficiency.

Other

In post marketing experience tumor lysis syndrome (TLS) has been reported in patients with malignancies, including hematological malignancies and solid tumors, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumors that have a high proliferative rate, high tumor burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.

Reproductive Health

See 7.1.1 Pregnancy

• Fertility

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

Corticosteroids have been shown to reduce fertility when administered to rats.

Sensitivity/Resistance

Allergic reactions (eg, angioedema) may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug. See 8 ADVERSE REACTIONS.

This medicine contains lactose produced from cow’s milk. Caution should be exercised in patients with a known or suspected hypersensitivity to cow’s milk or its components or other dairy products because it may contain trace amounts of milk ingredients.

7.1 Special Populations

7.1.1 Pregnancy

Corticosteroids readily cross the placenta. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits, have yielded an increase incidence of cleft palate in the off-spring (see 16 NON-CLINICAL TOXICOLOGY). There are no adequate and well-controlled studies in pregnant women. Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy or by women of child bearing potential only if clearly needed and the potential benefit justifies the potential risk to the mother and embryo or fetus.

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 labour and delivery. Some retrospective studies have found an increased incidence of low-birth weights in infants born of mothers receiving corticosteroids. In humans, the risk of low birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses.

Cataracts have been observed in infants born to mothers undergoing long-term treatment with corticosteroids during pregnancy.

7.1.2 Breastfeeding

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue the drug, taking into account the importance of the drug to the mother. This medicinal product should be used during breast feeding only after a careful assessment of the benefit risk ratio to the mother and infant.

7.1.3 Pediatrics

Pediatric patients may experience a decrease in their growth velocity observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose over the shortest period of time.

The growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Growth may be suppressed in children receiving long-term, daily-divided dose glucocorticoid therapy. The use of such a regimen should be restricted to the most serious indications.

Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.

High doses of corticosteroids may produce pancreatitis in children.

Hypertrophic cardiomyopathy was reported as one of the adverse effects of prophylactic or therapeutic administration of hydrocortisone to prematurely born infants and few months old babies (< 12 months), therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure must be performed (preferably two-dimensional echocardiography).

7.1.4 Geriatrics

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8 Adverse Reactions

8.1 Adverse Reaction Overview

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.

* Not a MedDRA PT

9 Drug Interactions

9.2 Drug Interactions Overview

Hydrocortisone is metabolized by 11β hydroxysteroid dehydrogenase type 2 (11β HSD2) and the cytochrome P450 (CYP) 3A4 enzyme. The CYP3A4 enzyme catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

9.4 Drug-Drug Interactions

CYP3A4 INHIBITORS - May decrease hepatic clearance and increase the plasma concentrations of hydrocortisone. In the presence of a CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, and grapefruit juice), the dose of hydrocortisone may need to be decreased to avoid steroid toxicity.

CYP3A4 INDUCERS - May enhance the metabolism of corticosteroids. May increase hepatic clearance and decrease the plasma concentrations of hydrocortisone. In the presence of a CYP3A4 inducer (e.g., barbiturates, rifampin, carbamazepine, phenobarbital, and phenytoin), the dose of hydrocortisone may need to be increased to achieve the desired response.

CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate, the hepatic clearance of hydrocortisone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration.

NON-CYP3A4-MEDIATED EFFECTS - Other interactions and effects that occur with hydrocortisone are described in Table 2 below.

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2. Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

Grapefruit or its juice are known to inhibit CYP3A and may increase hydrocortisone plasma concentration. Patients should avoid this fruit during CORTEF treatment. See 9.4 Drug-Drug Interactions.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Corticosteroids may suppress reactions to skin tests.

10 Clinical Pharmacology

10.1 Mechanism of Action

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining 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 responses to diverse stimuli.

10.2 Pharmacodynamics

Hydrocortisone (cortisol) is a corticosteroid (glucocorticoid) secreted by the adrenal cortex. In physiologic doses, it is administered to replace deficient endogenous hormones. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. In larger (pharmacologic) doses, hydrocortisone decreases inflammation and suppresses the immune response. It stimulates erythroid cells of the bone marrow, prolongs survival time of erythrocytes and platelets, and produces neutrophilia and eosinopenia. Hydrocortisone promotes protein catabolism, gluconeogenesis, and redistribution of fat from peripheral to central areas of the body. It reduces intestinal absorption and increases renal excretion of calcium.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their 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.

In pharmacologic doses, systemically administered glucocorticoids suppress release of corticotropin from the pituitary. The degree and duration of hypothalamic pituitary adrenal (HPA) axis suppression produced is highly variable among patients and depends on the dose, frequency and time of administration, and duration of therapy. If suppressive doses are administered for prolonged periods, the adrenal cortex atrophies and patients develop cushingoid features and respond to stress like patients with primary adrenocortical insufficiency. The duration of anti-inflammatory activity approximately equals the duration of HPA axis suppression. In one study, the duration of HPA axis suppression after a single oral dose of hydrocortisone 250 mg was 1.25 to 1.5 days.

10.3 Pharmacokinetics

The pharmacokinetics of hydrocortisone tablets in healthy male subjects demonstrated nonlinear kinetics following a single oral dose of 10, 30, and 50 mg of hydrocortisone.

Absorption: After oral administration of a 20 mg hydrocortisone tablet, hydrocortisone levels followed the classical one-compartment model. The absolute bioavailability averaged 96 ± 20%, indicating complete oral absorption.

Distribution: Hydrocortisone is extensively bound to the plasma proteins, corticosteroid binding globulin (transcortin) and albumin. With physiologic concentrations, it is bound primarily to transcortin and only 5 to 10% of cortisol in plasma is unbound. The plasma protein binding of hydrocortisone in humans is approximately 92%. The serum half-life of hydrocortisone tablets is 1.5 hours.

Metabolism:

Hydrocortisone is metabolized in most tissues, but primarily in the liver to biologically inactive compounds. Hydrocortisone is metabolized by 11β-HSD2 to cortisone, and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol, and 5α-tetrahydrocortisol. Cortisone can be converted to cortisol through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).

Hydrocortisone is also metabolized by CYP3A4 to 6β-hydroxycortisol (6β-OHF), and 6β-OHF varied from 2.8% to 31.7% of the total metabolites produced, demonstrating large inter-individual variability.

Elimination: The half-life of hydrocortisone may be prolonged in patients with hypothyroidism. Inactive metabolites are excreted by the kidneys, primarily as glucuronides and sulfates, but also as unconjugated products.

Negligible amounts are excreted in bile. Free-cortisol reduces to tetrahydrocortisol in the liver and inactivates by conjugation with glucuronic acid.

11 Storage, Stability and Disposal

Store between 15 and 30°C

12 Special Handling Instructions

This information is not available for this drug product.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Hydrocortisone

Chemical name: pregn-4-ene-3,20-dione,11,17,21-trihydroxy-, (11β)

Molecular formula and molecular mass: C₂₁H₃₀O₅ (362.46)

Structural formula:

O H H H OH CH₃ OH H CH3 OH O

Physicochemical properties: White to practically white, odourless, crystalline powder

14 Clinical Trials

The clinical trial data on which the original indication was authorized is not available.

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

Carcinogenesis: Hydrocortisone did not increase tumour incidences in male and female rats during a 2-year carcinogenicity study.

Genotoxicity: Corticosteroids, a class of steroid hormones that includes hydrocortisone, are consistently negative in the bacterial mutagenicity assay. Hydrocortisone and dexamethasone induced chromosome aberrations in human lymphocytes in vitro and in mice in vivo. Fludrocortisone (9α-fluorohydrocortisone, structurally similar to hydrocortisone) was negative in the human lymphocyte chromosome aberration assay.

Reproductive and Developmental Toxicity: Corticosteroids have been shown to reduce fertility when administered to rats.

Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to

20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced.

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation. With hydrocortisone, cleft palate was observed when administered to pregnant mice and hamsters during organogenesis.