Fludrocortisone (Acetate) See Introduction

PharmacoKinetics Oral absorption of Fludrocortisone (Acetate) is found to be 97% 2. Plasma protien binding is 75%. Presystemic metabolism is noted to be 90% and metabolism is reported Hepatic. Renal Excretion accounts for 80% and plasma half life is 0.5hr.

Fludrocortisone (Systemic)
VA CLASSIFICATION Primary: HS052 Secondary: CV900; DX900 Commonly used brand name(s): Florinef. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Corticosteroid (mineralocorticoid) antihypotensive (idiopathic orthostatic) diagnostic aid (renal tubular acidosis) Indications Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling. Accepted Note: Because of its marked effect of sodium retention, the use of fludrocortisone acetate in the treatment of conditions other then those indicated herein is not advised {59} Adrenocortical insufficiency, chronic primary (treatment) or Adrenocortical insufficiency, chronic secondary (treatment)Fludrocortisone is indicated as partial replacement therapy in the treatment of adrenocortical insufficiency in Addison's disease{59} . {02} {10} {13} {17} {24} {26} {29} {34} {35} {36} {45} Adrenogenital syndrome, congenital (treatment) Fludrocortisone is indicated in salt-losing forms of adrenogenital syndrome. {02} {10} {25} {26} {29} {40}

[Hypotension, idiopathic orthostatic (treatment)]1Fludrocortisone is used in conjunction with increased sodium intake in the treatment of idiopathic orthostatic hypotension. {39} {40} [Acidosis, in renal tubular disorders (diagnosis and treatment)]1Fludrocortisone is used in the treatment of Type IV renal tubular acidosis associated with hyporeninemic hypoaldosteronism. {39} {40} Fludrocortisone is also used as an aid in diagnosing the cause of the condition. Effectiveness of fludrocortisone therapy indicates that the condition is caused by hyporeninemic hypoaldosteronism rather than by renal tubular transport dysfunction. {25}
1

Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics Physicochemical characteristics: Molecular weight 422.49 {07} {12} Mechanism of action/Effect: Fludrocortisone acetate is an adrenal cortical steroid that has very high levels of mineralocorticoid activity and moderate levels of glucocorticoid activity. {10} {23} {29} {40} However, it is used only for its mineralocorticoid effects. {10} {23} {25} {40} Mineralocorticoids act on the distal tubules to increase potassium excretion, hydrogen ion excretion, and sodium reabsorption and subsequent water retention. {02} {10} {17} {29} Cation transport in other secretory cells is similarly affected; {10} excretion of water and electrolytes by the large intestine and by salivary and sweat glands is also altered, but to a lesser extent. At the cellular level, corticosteroids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA (messenger RNA) and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the physiological effects of these hormones. {10} Protein binding: High. Biotransformation: Hepatic, renal. Half-life: 3.5 hours (plasma); {01} {10} 1836 hours (biological). {10} Duration of action:

12 days. Elimination: Renal, mostly as inactive metabolites.

Precautions to Consider Carcinogenicity/Mutagenicity Adequate animal studies have not been conducted on the carcinogenicity or mutagenicity of fludrocortisone. {10} Pregnancy/Reproduction Pregnancy Studies on use of fludrocortisone during pregnancy have not been done in humans. {03} {10} {29} Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be closely observed for signs of hypoadrenalism. {10} {23} {17} {29} Adequate studies on use of fludrocortisone during pregnancy have not been done in animals. However, many corticosteroids have been shown to be teratogenic in laboratory animals at low doses. Teratogenicity of these agents in humans has not been demonstrated{59}{03} {10} {29} FDA Pregnancy Category C. {03} {10} {29} Breast-feeding Problems in humans have not been documented. {17} However, corticosteroids are distributed into breast milk and may cause unwanted effects in the infant such as growth suppression and inhibition of endogenous steroid production. {02} {10} {23} Pediatrics Although adequate and well-controlled studies have not been done in the pediatric population, corticosteroids may cause unwanted effects in children and growing adolescents, such as growth suppression and inhibition of endogenous steroid production. {10} {17} {23} {32} {33}

Geriatrics

Appropriate studies have not been performed in the geriatric population. One published report described the use of fludrocortisone in the treatment of severe hyponatremia that occurred following head injury in 3 geriatric patients in whom syndrome of inappropriate antidiuretic hormone (SIADH) had been ruled out as the cause of the hyponatremia. {42} {56} {57} Doses ranged from 0.1 to 0.4 mg of fludrocortisone per day. {42} {56} Drug interactions and/or related problems

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate) not necessarily inclusive ( = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. {58} Anabolic steroids {59} ( enhanced tendency toward edema {59})

Anticoagulants, oral {59} ( decreased prothrombin time response; monitor prothrombin levels; adjustment of anticoagulant dose may be required{59}) Antidiabetic drugs {59} ( diminished antidiabetic effect; monitor for symptoms of hyperglycemia; increased antidiabetic dose may be necessary {59}) Aspirin {59} ( increased ulcerogenic effect; decreased pharmacologic effect of aspirin; rarely salicylate toxicity may occur in patients who discontinue steroids after concurrent high-dose aspirin therapy; monitor salicylate levels or the therapeutic effect for which aspirin is given; adjustment in salicylate dose may be required {59}) Digitalis glycosides {10} {56} {57} (risk of cardiac arrhythmias or digitalis toxicity associated with hypokalemia may be increased; {10} {57} serum potassium concentrations and cardiac function should be monitored; {10} {57} potassium supplements may be required {10} {57} ) Estrogen {59} ( increased levels of corticosteroid-binding globulin, thereby increasing the bound (inactive) fraction; when estrogen therapy is initiated, an increase {61}{62} in corticosteroid dosage may be required {59}) Hepatic enzyme inducers {10} {40} {41} {43} {44} {52} {56} (See Appendix II ) (phenytoin and rifampin have been reported to increase 6-beta-hydroxylation of fludrocortisone, via induction of P-450 liver enzymes; {40} {41} {43} {44} {52} {56} fludrocortisone dosage increase may be required {10} {23} {40} {41} {43} {44} {52} {56}) Hypokalemia-causing medications {10} {40} {41} {46} {47} {48} {49} {56} (See Appendix II ) (risk of severe hypokalemia due to other hypokalemia-causing medications may be increased; {10} {40} {41} {56} monitoring of serum potassium concentrations and cardiac function and potassium supplementation may be required {10} {17} {23} {40} {41} {51} {56}) Lithium {53} {56} (in one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; {53} {56} increased fludrocortisone dose and dietary sodium

supplementation were required during concurrent use {53} {56}) Sodium-containing medications or foods {56} (concurrent use with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure; {56} adjustment of sodium intake may be required {02} {10} {17} {23} {56}) Vaccines {59} ( neurological complications and lack of antibody response {59})

Laboratory value alterations The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)not necessarily inclusive ( = major clinical significance): With physiology/laboratory test values Blood pressure (may be increased {10} {17} {23} {26} {29} {40} {42} {45}) (may be decreased due to increased blood volume {10} {17} {23} {42})

Hematocrit percentage

Nitroblue tetrazolium test {59} ( may show false-negative results {59}) ( may be decreased {59})

Prothrombin time response

Potassium {42} )

(serum concentration may be decreased due to increased potassium excretion {29}

Sodium (serum concentration may be increased due to sodium retention {02} {10} {17} {23} {26} {29} {42} )

Medical considerations/Contraindications The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate) not necessarily inclusive ( = major clinical significance).

Risk-benefit should be considered when the following medical problems exist Cardiac disease {02} or Congestive heart failure {17} {29} or Hypertension {02} {10} {17} {23} {29} or Peripheral edema or

 Renal function impairment, except when fludrocortisone is used to treat Type IV renal tubular acidosis {10} {29} (sodium- and fluid-retaining effects detrimental to these patients {10} {17} {23} ) Diverticulitis {59} Glomerulonephritis, acute {17} {29} Hepatic function impairment {10} {17} {23} {29} or Hypothyroidism {10} {17} {23} {29} (clearance of fludrocortisone may be decreased) Herpes simplex, ocular {59} ( possible corneal perforation {59})

Hyperthyroidism {10} {23} (clearance of fludrocortisone may be increased) Hypoprothrombinemia {59} ( use aspirin cautiously in conjunction with corticosteroids {59})

Intestinal anastomoses, fresh {59} Myasthenia gravis {59} Nephritis, chronic {17} {29} Osteoporosis {10} (may be exacerbated by increased calcium excretion {17} {29} {37}) Peptic ulcer, active or latent {59} Sensitivity to fludrocortisone Tuberculosis, active or latent (suppression of immune system could cause overwhelming infection {59}) Ulcerative colitis, unspecific {59} ( use corticosteroids with caution if there is a probability of impending perforation, abscess or other pyogenic infection {59})

Note: Canadian product information also lists the following medical conditions/contraindications for which risk-benefit should be considered if the medical problem exists: antibiotic resistant infections, convulsive disorders, Cushing's syndrome, diabetes mellitus, exanthema, metastatic carcinoma, thromboembolitic tendencies, thrombophlebitis, vaccinia and varicella {60}

Patient monitoring The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; = major clinical significance): Blood pressure determinations and Serum electrolyte concentrations {29}

(recommended at onset of therapy and at periodic

intervals during prolonged therapy {10} {17})

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Pharmacists Will Answer in Minutes! Questions Answered Every 9 Seconds. Drug-Interaction.JustAnswer.com Side/Adverse Effects The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)not necessarily inclusive: Note: Most adverse reactions of fludrocortisone are caused by the drug's mineralocorticoid activity (retention of sodium and water). When fludrocortisone is used in the small dosages recommended, the glucocorticoid side effects are not usually a problem, however these effects should be kept in mind, particularly when fludrocortisone is used over a prolonged period of time or in conjunction with cortisone or a similar glucocorticoid. {59}

Those indicating need for medical attention Incidence less frequent or rare Aggravating or masking of infections {59} anaphylaxis, generalized {02}{17}{29}{59}(cough; difficulty swallowing ; hives; redness and itching of skin; redness of conjunctivae; shortness of breath; swelling of nasal membranes, face, and eyelids) aseptic necrosis of femoral and humeral heads {59}{62} (decreased range of motion; joint pain; walking with a limp ) cardiac enlargement mineralocorticoid effect: see note above{59} congestive heart failure {59}(chest pain; decreased urine output; dilated neck veins; extreme fatigue; irregular breathing; irregular heartbeat; shortness of breath; swelling of face, fingers, feet, or lower legs; tightness in chest; troubled breathing; weight gain; wheezing ) mineralocorticoid effect: see note above{59} convulsions {59} cushingoid state, development of {59}(increased fat deposits on face, neck, and trunk) exophthalmos {59}(eyeballs bulge out of eye sockets)

facial erythema {59}(redness of face) glaucoma {59}(blindness; blurred vision; decreased vision; eye pain; headache; nausea or vomiting; tearing of eyes) glycosuria {59} growth suppression in children{59} hyperglycemia {59} hypertension {59}(blurred vision; dizziness, severe or continuing; nervousness; headache; pounding in the ears; slow or fast heartbeat)mineralocorticoid effect: see note above hypokalemic syndrome {02}{10}{17}{23}{26}{38}{40}{59}(irregular heartbeat; loss of appetite; muscle cramps or pain; nausea; severe weakness in arms, legs, or trunk ; vomiting) mineralocorticoid effect: see note above insulin requirements, increased {59}( patients taking insulin for diabetes may need to increase the amount they take) intracranial pressure with papilledema, increased usually after treatment{59} intraocular pressure, increased {59} latent diabetes mellitus manifestations {59}(blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; loss of consciousness; nausea; stomachache; sweating; troubled breathing; unexplained weight loss; vomiting) mental disturbances, severe {59}(anxiety, confusion, agitation or combativeness, depression, hallucinations, expressed fear of impending death) necrotizing angiitis {59}(chills; coughing; coughing up blood; headache; loss of appetite; pain in joints or muscles; shortness of breath; skin rash; unusual tiredness; unusual weight loss) negative nitrogen balance due to protein catabolism{59} oral hypoglycemic agents, increased requirements {59}(patients taking oral hypoglycemic agents for diabetes may need to increase the amount they take) osteoporosis {59}( back or rib pain; decrease in height)

pancreatitis {59}(bloating; chills; constipation; darkened urine; fast heartbeat; fever; indigestion; loss of appetite; nausea; pains in stomach, side, or abdomen, possibly radiating to the back; vomiting; yellow eyes or skin) pathologic fracture of long bones {59} peptic ulcer with possible perforation and hemorrhage {59}(bloody or black, tarry stools; abdominal or stomach pain or burning) peripheral edema {02}{10}{17}{23}{25}{26}{29}{37}{45}{59}(rapid weight gain; swelling of feet or lower legs)mineralocorticoid effect: see note above{59} posterior subcapsular cataracts {59} potassium loss mineralocorticoid effect: see note above{59} secondary adrenocortical and pituitary unresponsiveness particularly in times of stress{59} spontaneous fractures {59}(fractures in arms or legs without any injury) subcutaneous fat atrophy {59} suppressed reactions to skin tests {59} syncopal episodes {59}(fainting or lightheadedness when getting up from a lying or sitting position; unusually fast heartbeat palpitations) thrombophlebitis {59}( changes in skin color; pain; tenderness; swelling of foot or leg) ulcerative esophagitis {59}(chest pain; heartburn ) vertebral compression fractures {59}(fractures in the neck or back) wound healing, impaired {59}(problems with would healing )

Those indicating need for medical attention only if they continue or are bothersome Incidence less frequent or rare abdominal distention {59}(swelling of abdominal or stomach area; full or bloated feeling or pressure in the stomach) acneiform eruptions {59}(acne, pimples)

allergic skin rash {59} bruising {59} carbohydrate tolerance, decreased {59} dizziness {10}{23}{37}{59} ecchymoses {59}( bruising; large, flat, blue or purplish patches in the skin) headache, severe or continuing {02}{10}{17}{23}{45}{59} hirsutism {59}(unusual increase in hair growth) hives {59} hyperpigmentation of skin and nails {59}(change in color of skin or nails) insomnia {59}(sleeplessness; trouble sleeping; unable to sleep) loss of muscle mass {59} maculopapular rash {59}(redness or discoloration of skin) menstrual irregularities {59}(menstrual changes) muscle weakness {59} petechiae purpura {59}(small red or purple spots on skin) striae {59}(reddish purple lines on arms, face, legs, trunk, or groin) steroid myopathy {59} sweating, increased {59} thin, fragile skin {59} urticaria {59}(hives or welts; itching; redness of skin; skin rash)

Patient Consultation As an aid to patient consultation, refer to Advice for the Patient, Fludrocortisone (Systemic) In providing consultation, consider emphasizing the following selected information ( = major clinical significance): Before using this medication Conditions affecting use, especially: Sensitivity to fludrocortisone PregnancyInfants born to mothers who received substantial doses of corticosteroids during pregnancy require close observation for signs of hypoadrenalism Use in children and growing adolescentsMay cause growth suppression and inhibition of endogenous steroid production

Breast-feeding Corticosteroids are found in the breast milk of lactating women receiving systemic therapy with these agents. Caution should be exercised when fludrocortisone acetate is administered to a nursing woman Other medications, especially hypokalemia-causing medications, digitalis glycosides, hepatic enzyme inducers, or sodium-containing medications or food Other medical problems, especially cardiac disease, congestive heart failure, hypertension, or renal function impairment Proper use of this medication Importance of not taking more medication than the amount prescribed Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses {10} {23} Proper dosing Proper storage Precautions while using this medication Regular visits to physician to check progress during therapy Carrying medical identification card during long-term therapy

Side/adverse effects Signs of potential side effects, especially aggravating or masking of infections, generalized anaphylaxis, aseptic necrosis of femoral and humeral heads, {62}cardiac enlargement, congestive heart failure, convulsions, development of cushingoid state, exophthalmos, facial erythema, glaucoma, glycosuria, growth suppression, hyperglycemia, hypertension hypokalemic syndrome,increased insulin requirements, increased intracranial pressure with papilledema, increased intraocular pressure, latent diabetes mellitus manifestations, severe mental disturbances, negative nitrogen balance, increased requirements for oral hypoglycemic agents, osteoporosis, pancreatitis, pathologic fracture of long bones, peptic ulcer with possible perforation and hemorrhage, peripheral edema, posterior subcapsular cataracts, potassium loss, secondary adrenocortical and pituitary unresponsiveness, spontaneous fractures, subcutaneous fat atrophy, suppressed reactions to skin tests, syncopal episodes, thrombophlebitis, ulcerative esophagitis, vertebral compression fractures, impaired wound healing

General Dosing Information When used in the treatment of adrenocortical insufficiency or salt-losing forms of adrenogenital syndrome, fludrocortisone should be administered with appropriate glucocorticoid therapy such as 10 to 30 mg of hydrocortisone per day or 10 to 37.5 mg of cortisone per day. {35} {36} {40} {45} Sodium supplementation may also be necessary. {02} {10} {23}
{29} {36} {40} {45}

In the treatment of Type IV renal tubular acidosis, concurrent use of a diuretic may be necessary to decrease the risk of sodium and fluid retention, especially in patients with hypertension, congestive heart failure, or renal function impairment. Use of glucocorticoids{63} in immunosuppressant doses is associated with a higher risk of infection, with the potential for those infections to be of a more serious nature. {59} Care should be taken in adults and children to avoid exposure to viral infections, especially chickenpox and measles, if the patient has not already had the disease or been immunized against it. If exposed, therapy with varicella zoster immune globulin or pooled intravenous immunoglobulin may be a consideration{59} .

Oral Dosage Forms Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling. FLUDROCORTISONE ACETATE TABLETS USP

Usual adult and adolescent dose Adrenocortical insufficiency, chronic Oral, 100 mcg (0.1 mg) per day. {10} {13} {17} {23} {25} {29} {35} {36} {40} {45} Note: Dose should be reduced to 50 mcg (0.05 mg) per day if transient hypertension occurs. {10} {17} {23} {25} {29} {36} {40} Dosages of 100 mcg (0.1 mg) three times a week to 200 mcg (0.2 mg) once a day have been employed. {10} {17} {23} {25} {29} {34} {40} {45}

Adrenogenital syndrome, congenital Oral, 100 to 200 mcg (0.1 to 0.2 mg) per day. {10} {17} {23} {25} {29} {40} [Antihypotensive, idiopathic orthostatic]1 Oral, 50 to 200 mcg (0.05 to 0.2 mg) per day.

Usual pediatric dose Oral, 50 to 100 mcg (0.05 to 0.1 mg) per day. {16} {22} {40} Strength(s) usually available U.S.

100 mcg (0.1 mg) (Rx) [Florinef (scored) (lactose)]{10}{23} Canada

100 mcg (0.1 mg) (Rx) [Florinef (scored) (lactose)]{17}{29} Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), {10} {23} unless otherwise specified by manufacturer. Store in a well-closed container.