Fludrocortisone

380.45

380.45

204-833-2

U0476M545B

11318

DTXSID7023061

C71629

Crystals

H02AA02|H - Systemic hormonal preparations, excl. sex hormones and insulins

2937210000

94.8

0.3

Solid

1.1176 (estimate)

260-262 °C

564.7±50.0 °C(Predicted)

295.3±30.1 °C

1.584

H2O: 19mg/L(25 ºC)

Refrigerator

1.65X10-13 mm Hg at 25 deg C (est)

LD50 intraperitoneal in mouse: 170mg/kg

D23 +139° (c = 0.55 in 95% ethanol)

Henry's Law constant = 1.15X10-7 atm-cu m/mole at 25 °C (est)

DECOMPOSES @ 260-262 °C|ODORLESS OR PRACTICALLY ODORLESS; MP 225 °C; FINE, WHITE TO PALE-YELLOW POWDER /ACETATE/|Crystals, polymorphic, mp 233-234 °C (ocasionally mp 205-208 °C, resolidifying on further heating, then mp 226-228 °C). Specific optical rotation at 23 °C: 123 deg (c = 0.64 chloroform). UV max (ethanol): 238 nm (E 16800). Solubility (mg/mL): water 0.04; acetone 56; alc 20; chloroform 20; ether 4. /21-acetate/|Hydroxyl radical reaction rate constant = 1.08X10-10 cu cm/molec-sec at 25 °C (est)|Ozone rate constant = 1.14X10-17 cu cm/molec-sec at 25 °C (est)

63

22-26-36

Xn

Fludrocortisone acetate tablets should be stored in well-closed containers at room temperature; excessive heat should be avoided. /Fludrocortisone acetate/

P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P308+P313, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, P501

H302

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fludrocortisone acetate approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fludrocortisone acetate/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P308+P313, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral LD50 of fludrocortisone in rats is >1g/kg. Acute overdosage of fludrocortisone is likely to result in symptoms consistent with its adverse effect profile. Patients receiving a single large dose should be treated with plenty of water by mouth and should undergo monitoring of serum electrolytes, particularly potassium and sodium, and be treated appropriately for any developing imbalances.

Concurrent use /of sodium-containing foods or medications/ with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure;adjustment of sodium intake may be required.|In one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; increased fludrocortisone dose and dietary sodium supplementation were required during concurrent use.|Risk of severe hypokalemia /when fludrocortisone is used concurrently with hypokalemia-causing medications/; monitoring of serum potassium concentration and cardiac function and potassium supplementation may be required.|Phenytoin and rifampin have been reported to increase 6-beta-hydroxylation of fludrocortisone, via induction of p450 liver enzymes; fludrocortisone dosage increase may be required.|For more Interactions (Complete) data for FLUDROCORTISONE (24 total), please visit the HSDB record page.

Glucocorticoids should be used with caution in patients with hypothyroidism or cirrhosis, because such patients often show exaggerated response to the drugs. Glucocorticoids should be used with caution in psychotic patients or patients with hypertension or congestive heart failure. /Corticosteroids/|Because an apparent association has been suggested between use of corticosteroids and left ventricular free-wall rupture after a recent myocardial infarction, corticosteroids should be used with extreme caution in these patients. /Corticosteroids/|Because glucocorticoids increase susceptibility to and mask symptoms of infection, the drugs should not be used, except in life-threatening situations, in patients with viral infections or bacterial infections not controlled by anti-infectives. Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with untreated systemic fungal, bacterial, viral, or parasitic infections. Patients whose susceptibility to infection is high, such as those receiving glucocorticoids as immunosuppressive therapy, are especially likely to develop secondary infections. Patients receiving glucocorticoids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. Since glucocorticoid therapy can reactivate tuberculosis, treatment of latent tuberculosis infection should be included in the regimen of patients with a history of active tuberculosis undergoing prolonged glucocorticoid therapy. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary. Use of glucocorticoids in patients with active tuberculosis should be restricted to those with fulminating or disseminated tuberculosis in which glucocorticoids are used in conjunction with appropriate antimycobacterial chemotherapy. Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with clinical or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract. Since glucocorticoids can reactivate latent amebiasis, any patient who has been in the tropics or who has unexplained diarrhea should be evaluated for amebiasis to exclude these patients prior to initiating therapy. In the treatment of acute or disseminated tuberculosis, glucocorticoids should only be used as part of a total antituberculosis regimen. ... /Corticosteroids/|Corticosteroids should be used with caution in patients with active or latent peptic ulcer, diverticulitis, nonspecific ulcerative colitis (if there is a probability of impending perforation, abscess, or other pyogenic infection), and in those with recent intestinal anastomoses. Manifestations of peritoneal irritation following GI perforation may be minimal or absent in patients receiving glucocorticoids. /Corticosteroids/|Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered. /Corticosteroids/

Fludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin.

While data specific to fludrocortisone were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

Corticosteroids may be distributed into milk ... . /Corticosteroids/

Fludrocortisone is indicated as partial replacement therapy for primary or secondary adrenocortical insufficiency in Addison's disease. It is also indicated for the treatment of salt-losing androgenital syndrome.

Anti-Inflammatory Agents, Steroidal; Mineralocorticoids, Synthetic|Fludrocortisone is used in the treatment of Type IV renal tubular acidosis associated with hyporeninemic hypoaldosteronism. Fludrocortisone is also used as an aid in diagnosing the cause of the condition. Effectiveness of fludrocortisone therapy indicated that the condition is caused by hyporeninemic hypoaldosteronism rather than by renal tubular transport dysfunction. /NOT included in US product labeling/|Fludrocortisone is used in conjunction with increased sodium intake in the treatment of idiopathic orthostatic hypotension. /NOT included in US product labeling/|Fludrocortisone is indicated in salt-losing forms of adrenogenital syndrome. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for FLUDROCORTISONE (8 total), please visit the HSDB record page.

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.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|To evaluate tolerance of fludrocortisone in older patients with hypotensive disorders... 64 patients over 65 years (mean age 80 years) with one or more hypotensive disorders (orthostatic hypotension, vasodepressor carotid sinus syncope, and/or vasodepressor neurocardiogenic syncope /were given/ fludrocortisone in daily doses of 100 ug (corrected) (72%), 50 ug (corrected) (27%), and 200 ug (corrected) (one patient). ... During follow up, 13 patients died of unrelated causes. Of the remainder 33% discontinued fludrocortisone at a mean of five months. Reasons for discontinuing treatment were hypertension, five; cardiac failure, four; depression, three; edema, three; and unspecified, two. In those who continued treatment supine systolic and diastolic blood pressure did not differ significantly from baseline (follow up two to 21 months). Hypokalemia developed in 24% at a mean of eight months; in no case was treatment withdrawn because of hypokalemia. Fludrocortisone, even in low doses, is poorly tolerated in the long term in older patients with hypotensive disorders.|The mechanism of recumbent hypertension induced by fludrocortisone was studied in 7 patients with orthostatic hypotension. All showed increases in blood pressure in the recumbent and standing positions, and hypertensive levels were achieved on recumbency in 4 of them. Hypertensive retinopathy developed in 2 patients and cardiomegaly in one. Initial blood pressure elevations were associated with sodium retention and plasma volume expansion. However, with long term treatment, plasma volume decreased to control levels despite further blood pressure increases. Treatment did not affect plasma levels of catecholamines but did enhance pressor responsiveness to infused norepinephrine in some subjects. Hemodynamic studies indicated that hypertension in the recumbent position was related to increases in total peripheral vascular resistance and not to changes in cardiac output. Clinically, hypertension in the recumbent position is an important risk of fludrocortisone treatment in patients with orthostatic hypotension. This unusual model of chronic mineralocorticoid induced hypertension is not volume dependent but is related to increased peripheral vascular resistance.|For more Drug Warnings (Complete) data for FLUDROCORTISONE (13 total), please visit the HSDB record page.

Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous [aldosterone] in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy.

Substances that reduce or suppress INFLAMMATION. (See all compounds classified as Anti-Inflammatory Agents.)

Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the C_max to be 0.0012 to 0.20 μg/L with a T_max between 0.5 and 2 hours. The AUC_0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L.|Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route.|The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6.|Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h.|Elimination: Renal, mostly as inactive metabolites.|Oral: Rapidly and almost completely absorbed. Parenteral: Intramuscular: Freely soluble esters (sodium phosphate, sodium succinate) - Rapidly absorbed. Poorly soluble derivatives (acetate, acetonide, diacetate, hexacetonide, tebutate) - Slowly but completely absorbed. Local: Freely soluble esters - Less rapidly absorbed than with intramuscular injection. Poorly soluble derivatives - Slowiy but completely absorbed. /Corticosteroids (glucocorticoid effects - systemic)/

There exists is a paucity of information regarding the specific metabolic pathway _in vivo_ of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An _in vitro_ study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone).|STUDIED WERE KIDNEY SLICES, HOMOGENATES, & ISOLATED PERFUSED KIDNEYS. MAJOR METABOLITE: 20(EPSILON)-DIHYDRO-9ALPHA-FLUOROCORTISOL. ONLY 9ALPHA-FLUOROCORTISOL, NO METABOLITES, BOUND TO CYTOSOLIC RECEPTORS.

The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours.|> or = 3.5 hours (plasma); 18-36 hours (biological).

The main endogenous mineralocorticoid, aldosterone, is produced in the zona glomerulosa of the adrenal cortex - it acts on mineralocorticoid receptors in the kidneys to increase sodium reabsorption and potassium excretion, which in turn helps to regulate plasma electrolyte composition and blood pressure. In conditions of adrenal insufficiency, such as Addison’s disease, aldosterone is not produced (or is produced in insufficient quantities) and must be replaced by exogenous mineralocorticoids such as fludrocortisone. Fludrocortisone binding to mineralocorticoid receptors causes alterations to DNA transcription and translation of proteins that result in an increased density of sodium channels on the apical side of renal tubule cells and an increased density of Na⁺-K⁺-ATPase on the basolateral side. These increases in receptor density result in increased plasma sodium concentrations, and thus increased blood pressure, as well as a decreased plasma potassium concentration. Fludrocortisone may also exert a direct effect on plasma sodium levels via action at the Na⁺-H⁺ exchanger found in the apical membrane of renal tubule cells. Fludrocortisone also acts on glucocorticoid receptors, albeit with a much lower affinity - the glucocorticoid potency of fludrocortisone is approximately 5-10 times that of endogenous cortisol, whereas its mineralocorticoid potency is 200-400 times greater.|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.|Mineralocorticoids act on the distal tubules to increase potassium excretion, hydrogen ion excretion, and sodium reabsorption and subsequent water retention. Cation transport in other secretory cells is similarly affected; excretion of water and electrolytes by the large intestine and by salivary and sweat glands is also altered, but to a lesser extent.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered. /Corticosteroids/|/CASE REPORTS/ The ... case of congestive cardiac failure in a child with Addison's disease secondary to fludrocortisone therapy is presented. A renal adaptation to compensate for chronic salt and water deprivation is suggested as a possible mechanism for the development of congestive cardiac failure in this patient.|/CASE REPORTS/ A severe metabolic alkalosis with compensatory respiratory acidosis and hypokalemia were reported in a 71-yr-old female patient following one yr of treatment with fludrocortisone, 0.2 mg/day, for postural hypotension. Following therapy which included diuretic administration, potassium supplementation and administration of spironolactone, the patient's clinical condition improved.

9 alpha Fludrohydrocortisone

Oral: Tablets: 0.1 mg Florinef Acetate (scored), (Monarch), Fludrocortisone Acetate Tablets (scored), (Barr), Fludrocortisone Acetate Tablets (scored), (Global). /Fludrocortisone acetate/

ANALYSIS OF FLUDROCORTISONE PREPARATIONS BY HPLC.|DETERMINATION OF FLUDROCORTISONE ACETATE TABLET DISSOLUTION RATE BY A SEMIAUTOMATED HPLC SYSTEM.|Analyte: fludrocortisone acetate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /fludrocortisone acetate/|Analyte: fludrocortisone acetate; matrix: chemical purity; procedure: visible absorption spectrophotometry at 525 nm with comparison to standards /fludrocortisone acetate/|For more Analytic Laboratory Methods (Complete) data for FLUDROCORTISONE (9 total), please visit the HSDB record page.

Analyte: fludrocortisone; matrix: blood (serum), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm|Analyte: fludrocortisone; matrix: urine; procedure: reversed-phase liquid chromatography-tandem mass spectrometry|Analyte: fludrocortisone; matrix: urine; procedure: gas chromatography-mass spectrometry with electron impact ionization; limit of detection: 5 ng/mL|Analyte: fludrocortisone; matrix: urine; procedure: high-performance liquid chromatography with mass spectrometric detection; limit of detection: 5 ng/mL

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Lipids -> Sterol Lipids [ST] -> Steroids [ST02] -> C21 steroids (gluco/mineralocorticoids, progestogins) and derivatives [ST0203]|Pharmaceuticals