Florinef Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

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

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics .............................................................................................................. 4

1.2 Geriatrics .............................................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 4

4.1 Dosing Considerations .......................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment ..................................................... 5

4.4 Administration ...................................................................................................... 5

5 OVERDOSAGE .............................................................................................................. 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 6

7 WARNINGS AND PRECAUTIONS .................................................................................. 6

7.1 Special Populations ............................................................................................. 10

7.1.1 Pregnant Women ........................................................................................... 10

7.1.2 Breast-feeding ................................................................................................ 10

7.1.3 Pediatrics ........................................................................................................ 10

7.1.4 Geriatrics ........................................................................................................ 10

8 ADVERSE REACTIONS ................................................................................................ 10

8.1 Adverse Reaction Overview ................................................................................ 10

9 DRUG INTERACTIONS ................................................................................................ 12

9.2 Drug Interactions Overview ................................................................................ 12

9.3 Drug-Behavioural Interactions ............................................................................ 12

9.4 Drug-Drug Interactions ....................................................................................... 12

9.5 Drug-Food Interactions ....................................................................................... 16

9.6 Drug-Herb Interactions ....................................................................................... 16

9.7 Drug-Laboratory Test Interactions ...................................................................... 16

10 CLINICAL PHARMACOLOGY ....................................................................................... 16

10.1 Mechanism of Action .......................................................................................... 16

10.2 Pharmacodynamics ............................................................................................ 17

10.3 Pharmacokinetics ............................................................................................... 17

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 17

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 18

PART II: SCIENTIFIC INFORMATION ....................................................................................... 19

13 PHARMACEUTICAL INFORMATION ............................................................................ 19

14 CLINICAL TRIALS ........................................................................................................ 19

15 MICROBIOLOGY ........................................................................................................ 19

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 19

PATIENT MEDICATION INFORMATION .................................................................................. 21

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

FLORINEF (fludrocortisone acetate tablets) is indicated:

• as a partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison’s disease.
• for the treatment of salt-losing adrenogenital syndrome.

1.1 Pediatrics

Pediatrics (<18 years old): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics (>65 years old): No data are available to Health Canada.

2 CONTRAINDICATIONS

FLORINEF is contraindicated in patients:

• who are hypersensitive to this drug 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.
• with systemic fungal infections.
• administered with live or live, attenuated vaccines while receiving immunosuppressive doses of corticosteroids.
• with herpes simplex of the eye, except when used for short-term or emergency therapy as in acute sensitivity reactions.
• with vaccinia and varicella infections, except when used for short-term or emergency therapy as in acute sensitivity reaction.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• The lowest possible dose should be used to control the condition being treated, and a gradual reduction in dosage should be made when possible (see 7 WARNINGS AND PRECAUTIONS, General).
• Dosage depends on the severity of the disease and the response of the patient. Patients should be continually monitored for signs that indicate dosage adjustment is needed, such as remission or exacerbations of disease and stress (surgery, infection, trauma) (see 7 WARNINGS AND PRECAUTIONS, General).

4.2 Recommended Dose and Dosage Adjustment

Addison’s disease

The recommended oral dose is one tablet (0.1 mg) once daily, although dosage ranging from one tablet (0.1 mg) three times a week to two tablets (0.2 mg) once daily may be used based on individual patient needs.

If treatment-associated hypertension develops, the dose should be reduced to 0.05 mg daily.

Fludrocortisone is preferably administered in conjunction with cortisone (10 to 37.5 mg daily in divided doses) or hydrocortisone (10 to 20 mg daily in divided doses).

Salt-losing adrenogenital syndrome

The recommended oral dose is one tablet (0.1 mg) to two tablets (0.2 mg) once daily.

Pediatrics (< 18 years of age)

Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

4.4 Administration

• FLORINEF is administered orally.
• FLORINEF should not be taken with grapefruit juice (see 9.5 Drug-Food Interactions).

5 OVERDOSAGE

Overdoses following Chronic Administration

Development of hypertension, edema, hypokalemia, significant increase in weight, and cardiomegaly may be signs of excessive dosage of fludrocortisone. When these are noted, administration of the drug should be discontinued, after which the symptoms will usually subside within several days; subsequent treatment with fludrocortisone, if necessary, should be resumed at a reduced dose. Muscle weakness due to excessive potassium loss may develop and can be treated with potassium supplements.

Monitoring of blood pressure and serum electrolytes can reduce the likelihood of consequences of excessive dosage (see 7 WARNINGS AND PRECAUTIONS, General).

Overdoses following Acute Administration

For large, acute overdoses, treatment includes gastric lavage or emesis and usual supportive measures.

Careful monitoring of serum electrolytes is essential, with particular consideration being given to the need for administration of potassium chloride and restriction of dietary sodium intake (see 7 WARNINGS AND PRECAUTIONS, General).

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

FLORINEF tablets are available as white, round, biconvex tablets, scored on one side and with “RPC” over “059” engraved on the other side.

FLORINEF tablets are supplied in bottles of 100 counts.

7 WARNINGS AND PRECAUTIONS

General

Because of its marked effect on sodium retention, the use of fludrocortisone in the treatment of conditions other than those indicated herein is not advised.

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

Adverse reactions to corticosteroids may be produced by too rapid withdrawal or by continued use of large doses. Corticosteroids should therefore be withdrawn gradually and tapered off over weeks and months according to the dose and duration of treatment.

Carcinogenesis and Mutagenesis

Corticosteroids should be used with caution in patients with metastatic carcinoma.

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

Cardiovascular

Corticosteriods should be used with caution in patients with hypertension, congestive heart failure, thromboembolitic tendencies and thrombophlebitis.

Moderate and high 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 high doses. However, since fludrocortisone is a potent mineralocorticoid, both the dosage and salt intake should be carefully monitored in order to avoid the development of hypertension, edema, or weight gain (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

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, visual disturbances and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.

Endocrine and Metabolism

To avoid drug induced adrenal insufficiency, supportive dosage may be required in times of stress (such as trauma, surgery, or severe illness) both during treatment with fludrocortisone and for a year afterwards.

There is an enhanced corticosteroid effect in patients with hypothyroidism. Changes in thyroid status of the patient may necessitate adjustment in adrenocorticoid dosage.

Corticosteriods should be used with caution in patients with Cushing’s syndrome and diabetes mellitus.

FLORINEF contains lactose. Its use is not recommended in patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Pheochromocytoma crisis

Several life-threatening and fatal cases of pheochromocytoma crisis has been reported following administration of systemic corticosteroids to patients with suspected or identified pheochromocytoma. Use of corticosteroids in these patients should only be considered after an appropriate risk/benefit evaluation.

Gastrointestinal

Corticosteroids, when used as direct or adjunctive therapy, should be used with caution in patients with diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer (or a history of peptic ulcer) and non-specific ulcerative colitis if there is a probability of impending perforation, abscess, or other pyogenic infection.

Hematologic

Acetylsalicylic acid (ASA) should be used with caution in conjunction with corticosteroids in patients with hypoprothrombinemia.

Hepatic/Biliary/Pancreatic

Hepatobiliary disorders have been reported which may be reversible after discontinuation of therapy. Therefore, appropriate monitoring is required.

Corticosteroids may have an increased effect in patients with hepatic disease since the metabolism and elimination of these drugs are significantly decreased in these patients.

Fludrocortisone should therefore be used with caution in patients with hepatic disease.

Immune

Corticosteroids may mask some signs of infection with any pathogen, including viral, bacterial, fungal, protozoan or helminthic, in any location of the body, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

Corticosteroids should be used with caution in patients with vaccinia, varicella and antibiotic resistant infections.

If an infection occurs during fludrocortisone therapy, it should be promptly controlled by a suitable therapy.

Fungal infections

Fludrocortisone is contraindicated in patients with systemic fungal infections (see 2 CONTRAINDICATIONS).

Viral infections

Viral infections such as chicken pox, smallpox, measles, herpes zoster (shingles), or threadworm infestations, for example, can have a more serious or even fatal course in nonimmune children or adults on corticosteroids.

Vaccination

Patients should not be vaccinated or immunized while on corticosteroid therapy, especially on high doses, because of a lack of antibody response predisposing to medical complications, particularly neurological ones.

Tuberculosis

The use of fludrocortisone in patients with 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 since reactivation of the disease may occur. During prolonged corticosteroid therapy these patients should receive chemoprophylaxis.

Monitoring and Laboratory Tests

Monitoring of serum electrolytes such as sodium, potassium and calcium is recommended when taking fludrocortisone for an extended period.

Corticosteroids may suppress reactions to skin tests (see 8.1 Adverse Reaction Overview and 9.7 Drug Laboratory Test Interactions).

Musculoskeletal

All corticosteroids increase calcium excretion., which may predispose to osteoporosis or aggravate pre-existing osteoporosis.

Corticosteroids should be used with caution in patients with osteoporosis, or who are at risk of osteoporosis.

Neurologic

Corticosteroids should be used with caution in patients with convulsive disorders and myasthenia gravis.

Ophthalmologic

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, exophthalmos, or increased intraocular pressure, which may result in glaucoma and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Corticosteroids should be used with caution in patients with ocular herpes simplex because of possible corneal perforation.

Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.

If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy.

Psychiatric

Psychiatric disturbances may appear when corticosteroids are used. These may include euphoria, insomnia, mood swings, personality changes, and severe depression and frank psychotic symptoms. Existing emotional instability or psychotic tendencies may also be aggravated by corticosteroids.

The use of antidepressant drugs does not relieve and may exacerbate adrenocorticoid-induced mental disturbances.

Renal

Corticosteroids should be used with caution in patients with renal insufficiency, acute glomerulonephritis, and chronic nephritis.

Reproductive Health: Female and Male Potential

• Fertility

It is not known if fludrocortisone acetate impairs human fertility.

However, corticosteroids have been shown to reduce fertility when administered to rats (see 16 NONCLINICAL TOXICOLOGY).

• Teratogenic Risk

It is not known if fludrocortisone acetate causes any teratogenic effect on the human fetus.

However, corticosteroids have been shown to cause deleterious effects on the fetus’ and infant’s body, brain, neuroendocrine function, and behavior in some animal species. Oral cleft palate was also observed in mice and hamsters (see 16 NONCLINICAL TOXICOLOGY).

Skin

Corticosteroids should be used with caution in patients with exanthema.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled human reproduction studies in pregnant women and women of childbearing potential taking systemic corticosteroids. As such, use of corticosteroids in this population requires that the possible benefits of the drug be weighed against the potential hazards to the mother or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Maternal treatments should be carefully documented in the infant’s medical records to assist in follow-ups.

7.1.2 Breast-feeding

There are no adequate and well-controlled human reproduction studies in nursing mothers taking systemic corticosteroids. As such, use of corticosteroids in this population requires that the possible benefits of the drug be weighed against the potential hazards to the mother or nursing infant.

Other systemic corticosteroids have been found to be excreted in human milk in low doses.

7.1.3 Pediatrics

Pediatrics (<18 years old): Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed (see 8 ADVERSE REACTIONS).

7.1.4 Geriatrics

Geriatrics (>65 years old): No data are available to Health Canada.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Most adverse reactions are caused by the drug’s mineralocorticoid activity (retention of sodium and water) and include hypertension, edema, congestive heart failure, cardiomegaly, blood potassium decreased, and hypokalemic alkalosis.

When fludrocortisone is used at the recommended small dosages, the side effects seen with cortisone and its derivatives are not usually an issue.

The inclusion of the following list of adverse reactions does not necessarily indicate that the specific event has been observed with this particular formulation.

However, the following adverse reactions should be kept in mind, particularly when this agent is used over a prolonged period of time or in conjunction with cortisone or a similar glucocorticoid:

Table 2 – Potential Adverse Reactions Associated with Systemic Corticosteroids

Adverse Reactions

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Fludrocortisone acetate is primarily metabolized by cytochrome P450 (CYP) 3A4 enzymes. CYP3A enzymes, which are known to be present in critical tissues such as the liver, are responsible for the metabolism of many other compounds, including other corticosteroids. Co-administration of drugs that induce or inhibit CYP3A4 enzymes can therefore impact the metabolism and clearance of fludrocortisone.

9.3 Drug-Behavioural Interactions

Interactions with individual behaviour risks such as alcohol consumption, sexual activity and smoking have not been established.

9.4 Drug-Drug Interactions

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 3 - Established or Potential Drug-Drug Interactions

Legend: T = Theoretical

9.5 Drug-Food Interactions

Grapefruit or its juice are known to inhibit CYP3A and may increase fludrocortisone plasma concentration. Patients should avoid this fruit during FLORINEF treatment.

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

Fludrocortisone is a synthetic corticosteroid with potent mineralocorticoid activity. The major effect of mineralocorticoids is the regulation of electrolyte excretion in the kidney.

10.2 Pharmacodynamics

The physiologic action of fludrocortisone is similar to that of hydrocortisone. However, the effects of fludrocortisone, particularly on electrolyte balance, but also on carbohydrate metabolism, are considerably heightened and prolonged. In small oral doses, fludrocortisone produces marked sodium retention and increased urinary potassium excretion. It also causes a rise in blood pressure, apparently because of these effects on electrolyte levels. In larger doses, fludrocortisone inhibits endogenous adrenal cortical secretion, thymic activity, and pituitary corticotropin excretion, promotes the deposition of liver glycogen and, unless protein intake is adequate, induces negative nitrogen balance.

10.3 Pharmacokinetics

Absorption

Absorption of fludrocortisone occurs predominantly in the gastrointestinal tract. After oral administration, fludrocortisone undergoes extensive first-pass metabolism in the liver, resulting in low systemic bioavailability.

Absorption of fludrocortisone can be influenced by various factors, such as food intake and gastric pH. High-fat meals can enhance its absorption, while antacids may decrease its bioavailability by altering the gastric pH.

Distribution

Fludrocortisone, mostly as inactive metabolites, binds extensively to plasma proteins, primarily albumin, with approximately 70-80% of the drug bound. The binding to plasma proteins reduces the amount of free, biologically active fludrocortisone available. The drug can cross the blood-brain barrier, leading to its effects on the central nervous system and regulation of fluid and electrolyte balance.

Metabolism

Fludrocortisone is primarily metabolized in the liver through various enzymatic pathways, including hydrolysis, reduction, and oxidation. The cytochrome P450 enzyme system, particularly CYP3A4, plays a significant role in the metabolism of fludrocortisone. Co-administration of drugs that induce or inhibit CYP3A4 can potentially alter the metabolism and clearance of fludrocortisone.

Elimination

The elimination of fludrocortisone occurs primarily through hepatic metabolism and subsequent excretion in the urine. The pharmacokinetic half-life of fludrocortisone is approximately 5.5 hours. The pharmacodynamic half-life of fludrocortisone is approximately 18 to 36 hours. The duration of action is 1 to 2 days.

11 STORAGE, STABILITY AND DISPOSAL

Store refrigerated (2°C and 8°C).

Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: fludrocortisone acetate

Chemical name: 9α-fluoro-11β,17α,21-trihydroxypregn-4-ene-3,20-dione 21-acetate

Molecular formula and molecular mass: C₂₃H₃₁FO₆; 422.5 g/mol

Structural formula:

Physicochemical properties: white to practically white, crystalline powder

Solubility: practically insoluble in water

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

Reproductive and Developmental Toxicology

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.

Three-week old female mice were administered with pregnant horse serum gonadotropin (PMSG) and 0.2 mg/µL cortisol/corticosterone intraperitoneally at intervals of 8 hours. Blood, ovaries, or ovarian granulosa cell samples were collected at 24 h, 48 h and 55 h after PMSG injection. Significant decrease in ovulation rates, ovarian weight, ovarian index, the number of secondary follicles and mature follicles, levels of estrogen and progesterone, and mRNA expression of steroid synthase-related genes were observed.

Corticosteroids have been shown to be teratogenic in many species.

In animal reproduction studies, glucocorticoids have been shown to have deleterious effects on the body (organ weight reduction, delayed growth and development), the brain and neuroendocrine function (neuronal degeneration, alterations of neuroendocrine regulation) and the behavior (impairment in muscle coordination and muscle tone) of fetuses and offspring of mothers who were dosed prenatally.

Corticosteroids were observed to cause cleft palate when administered to pregnant mice and hamsters during organogenesis.