Advice
Overview for healthcare professionals
Overview for healthcare professionals
Regulatory status of fludrocortisone
Fludrocortisone acetate (Florinef) 100 micrograms tablets are licensed in the UK for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for treating salt-losing adrenogenital syndrome. Fludrocortisone does not have marketing authorisation in the UK for treating postural hypotension, so use for this indication is off label.
In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using fludrocortisone outside its authorised indications.
Evidence statements
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One small double-blind, placebo-controlled, crossover randomised controlled trial (RCT) (Campbell et al. 1975) in 6 adult males with postural hypotension as a result of diabetic autonomic neuropathy found that 100 micrograms fludrocortisone taken twice daily for 3 weeks increased both tilted position and supine systolic blood pressure (SBP) [~30–40 mmHg] and tilted position diastolic blood pressure (DBP) [~10 mmHg] compared with placebo.
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One small double-blind crossover RCT (Schoffer et al. 2007) in 17 adults with postural hypotension and Parkinson's disease found a statistically significant improvement in the orthostatic domain of the Composite Autonomic Symptom Scale (COMPASS\u2011\OD) with 3 weeks of 100 micrograms fludrocortisone daily plus non-pharmacological treatment compared with non-pharmacological treatment alone. The clinical significance of this improvement (a decrease in the mean score of 3 points; on a 16‑point scale) is unclear.
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One placebo-controlled RCT (Rowe et al. 2001) in 100 adults with chronic fatigue syndrome found no significant effect of 9 weeks of fludrocortisone titrated to 100 micrograms daily compared with placebo on global wellness score, supine SBP and DBP.
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Safety of fludrocortisone use has not been adequately assessed in these 3 RCTs. Side effects reported in the studies included ankle oedema, weight increase, electrolyte disturbances, hypertension, depression, abdominal discomfort, nausea, headache, light-headedness and dizziness.
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Withdrawals were higher with fludrocortisone than placebo in the longest trial (Rowe et al. 2001) (26% of people taking fludrocortisone withdrew compared with 16% receiving placebo).
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The longer-term (more than 9 weeks) efficacy and safety of fludrocortisone has not been studied in these RCTs.
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A prospective observational study (Hussain et al. 1996) over a mean follow-up of 12 months (range 2–21 months) in 64 older adults with 1 or more hypotensive disorders (including 17 people given fludrocortisone for postural hypotension) reported that 38 people (59.4%) experienced side effects and 17 stopped treatment after a mean of 5 months. However, the observational nature of this study in a mixed population with 1 or more hypotensive disorders and the lack of a control arm limit the conclusions that can be drawn.
Summary of the evidence
This section gives a brief summary of the main evidence. A more comprehensive analysis is given in the Evidence review sections.
Efficacy
All of the trials identified were small, with 100 participants or fewer. Two double-blind, crossover RCTs examined the efficacy and safety of fludrocortisone for treating postural hypotension (postural drop of at least 20–30 mmHg in systolic blood pressure [SBP] or 10 mmHg in diastolic blood pressure [DBP]) in adult males with autonomic diabetic neuropathy (n=6; Campbell et al. 1975; when compared with placebo) and adults with Parkinson's disease (n=17; Schoffer et al. 2007; when compared with domperidone; off-label use) for 3 weeks.
There was no direct comparison between fludrocortisone and domperidone in Schoffer et al. (2007). Doses of fludrocortisone in these trials were 100 micrograms taken 1 or 2 times daily. Both Schoffer et al. (2007) and Campbell et al. (1975) investigated postural drop using a head-up tilt-test, in which the person is tilted head-up to at least a 60° angle on a tilt table.
One additional double-blind randomised placebo-controlled trial (Rowe et al. 2001; n=100) was identified comparing 9 weeks' treatment with fludrocortisone (titrated to 100 micrograms daily) with placebo in adults with chronic fatigue syndrome (see Evidence review: efficacy for details).
Results of the RCT in men with autonomic diabetic neuropathy (Campbell et al. 1975) found that 3 weeks' treatment with 100 micrograms fludrocortisone daily increased both tilted position and supine SBP (~30–40 mmHg) and tilted position DBP (~10 mmHg) compared with placebo.
A total of 5 participants were analysed with 1 excluded because of 'default' while taking fludrocortisone (Campbell et al. 1975). No further information is provided about why this participant dropped out. Out of 5 participants, 4 were reported to notice a marked improvement in their symptoms of postural hypotension while taking fludrocortisone. However, it is not reported how this was assessed.
The RCT in people with Parkinson's disease (Schoffer et al. 2007) had 2 phases. Phase 1 evaluated non-pharmacological treatment for postural hypotension, and phase 2 evaluated drug treatment (fludrocortisone and domperidone). Non-pharmacological treatment was continued throughout the course of the study and then an analysis was performed of non-pharmacological treatment plus drug treatment compared with non-pharmacological treatment alone. It found that there was a statistically significant improvement (a decrease in the mean score of 3 points; on a 16‑point scale) in the orthostatic domain of the Composite Autonomic Symptom Scale (COMPASS-OD) after 3 weeks' treatment with 100 micrograms fludrocortisone daily compared with non-pharmacological treatment alone. There was a very slight improvement (an increase in the mean score of 0.2; on a scale of +3 to −3) in the global impression of change score after treatment with fludrocortisone compared with non-pharmacological treatment alone; no statistical analysis reported. The authors concluded that there was a trend towards reduced blood pressure drop on tilt-table testing with both fludrocortisone and domperidone. However, no statistical analysis of the tilt-table test results was provided (see table 2 for results).
The RCT in adults with chronic fatigue syndrome (Rowe et al. 2001) found no statistically significant difference between fludrocortisone and placebo for improvement in global wellness score and mean supine SBP and DBP.
Table 1 Summary of Campbell et al. (1975) (adult males with diabetic autonomic neuropathy and postural hypotension)
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Fludrocortisone |
Placebo |
Analysis |
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Campbell et al. (1975): double-blind randomised crossover trial |
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Dose |
100 micrograms oral tablets 2 times daily |
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Randomised |
n=6 |
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Efficacy |
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Analysed |
n=5 |
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Supine SBP, mmHg, mean (SD) |
180 (26) |
149 (21) |
p<0.05 |
|
Tilted position SBP, mmHg, mean (SD) |
154 (29) |
110 (16) |
p<0.005 |
|
Mean supine SBP versus mean tilted position SBP |
No statistically significant difference between mean supine and tilted position SBP with fludrocortisone (p<0.10) |
Statistically significant difference between mean supine and tilted position SBP with placebo (p<0.001) |
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|
Supine DBP, mmHg, mean (SD) |
95 (17) |
87 (10) |
NS, p value not reported |
|
Tilted position DBP, mmHg, mean (SD) |
88 (11) |
76 (4) |
p<0.05 |
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Mean supine DBP versus mean tilted position DBP |
No statistically significant difference between mean supine and tilted position DBP with fludrocortisone (p value not reported) |
Statistically significant difference between mean supine and tilted position DBP with placebo (p<0.02) |
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|
Supine heart rate, beats per minute, mean (SD) |
76 (12) |
78 (10) |
NS, p value not reported |
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Tilted position heart rate, beats per minute, mean (SD) |
86 (20) |
97 (18) |
p<0.001 |
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Safety |
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Discontinuation or withdrawal from study |
n=1/6 |
n=0/6 |
1 person is reported to have 'defaulted' while taking fludrocortisone. No further information is provided. |
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AE: pitting ankle oedema |
n=2/5 (within 1 week of starting treatment) |
n=0/5 |
Both people had intermittent proteinuria and low plasma albumin |
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AE: self-reported frontal headache and breathlessness |
n=1/5 |
n=0/5 |
The person had intermittent proteinuria and low plasma albumin |
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Serum sodium, mmol/litre, mean (SD) |
142.6 (2.2) |
140.6 (1.3) |
p<0.02 |
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Serum potassium, mmol/litre, mean (SD) |
3.6 (0.4) |
4.3 (0.2) |
p<0.01 |
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Body weight, kg (SD) |
71.6 (9.3) |
68.9 (9.3) |
p<0.001 |
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Total plasma volume, ml (SD) |
3286 (234) |
2957 (171) |
p<0.02 |
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Abbreviations: AE, adverse event(s); DBP, diastolic blood pressure n, number of patients; NS, non-significant; SBP, systolic blood pressure; SD, standard deviation. |
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Table 2 Summary of Schoffer et al. (2007) (adults with Parkinson's disease and postural hypotension)
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Fludrocortisone plus non-pharmacological treatment |
Domperidone plus non-pharmacological treatment |
Non-pharmacological treatment alone |
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Schoffer et al. (2007): double-blind randomised crossover trial |
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Dose |
100 micrograms daily |
10 mg 3 times daily |
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Randomised |
n=17 |
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Efficacy |
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Analysed |
n=13 |
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Primary outcome measures |
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COMPASS-OD scorea expressed as mean (SD) (median; range) |
6 (3) (6; 1 to 10) Statistically significant improvement compared with non-pharmacological treatment alone (p=0.02) |
7 (2) (6; 3 to 11) Statistically significant improvement compared with non-pharmacological treatment alone (p=0.04) |
9 (3) (9; 5 to 15) |
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CGI scoreb expressed as mean (SD) (median; range) |
0.6 (1.2) (1; −1 to 2) No statistical analysis reported for this outcome measure |
0.9 (1.2) (1; −2 to 2) No statistical analysis reported for this outcome measure |
0.4 (1) (0; −2 to 2) |
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Drop in SBP, mmHg, at 3 minutes of tilt table, expressed as mean (SD) (median; range) |
18 (24) (8; −8 to 64) No statistical analysis reported for tilt-table testing |
18 (23) (5; −4 to 57) No statistical analysis reported for tilt-table testing |
21 (20) (17; −15 to 48) |
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Maximal drop in SBP, mmHg, during 5 minutes of tilt table, expressed as mean (SD) (median; range) |
30 (23) (24; −2 to 64) No statistical analysis reported for tilt-table testing |
28 (21) (19; 5 to 61) No statistical analysis reported for tilt-table testing |
35 (23) (32; 6 to 68) |
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Drop in DBP, mmHg, at 3 minutes of tilt table, expressed as mean (SD) (median; range) |
8 (13) (8; −11 to 33) No statistical analysis reported for tilt-table testing |
7 (15) (0; −10 to 36) No statistical analysis reported for tilt-table testing |
7 (7) (8; −4 to 18) |
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Maximal drop in DBP, mmHg during 5 minutes of tilt table, expressed as mean (SD) (median; range) |
18 (12) (20; 0 to 35) No statistical analysis reported for tilt-table testing |
14 (15) (6; −1 to 40) No statistical analysis reported for tilt-table testing |
17 (10) (20; 3 to 37) |
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Supine SBP, mmHg, expressed as mean (SD) (median; range) |
134 (24) (137; 100 to 165) No statistical analysis reported for tilt-table testing |
138 (27) (125; 107 to 189) No statistical analysis reported for tilt-table testing |
138 (23) (139; 107 to 175) |
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Safety (n=17) |
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Discontinuation or withdrawal from study |
n=1 |
n=3 |
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Total patients reporting AEs |
n=6 No statistical analysis reported |
n=5 No statistical analysis reported |
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Abbreviations: AE, adverse event(s); CGI, clinical global impression of change; COMPASS-OD, orthostatic domain of the Composite Autonomic Symptom Scale; DBP, diastolic blood pressure; n, number of patients; SBP, systolic blood pressure; SD, standard deviation. a COMPASS‑OD: a series of weighted questions relating specifically to orthostatic hypotension. Maximum score is 16, with higher scores indicating more severe symptoms. b CGI: Global impression of change score that focuses on orthostatic symptoms (+3=very much improved, +2=much improved, +1=minimally improved, 0=no change, −1=minimally worse, −2=much worse, −3=very much worse). |
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Table 3 Summary of Rowe et al. (2001) (people with chronic fatigue syndrome and neurally mediated hypotension)
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Fludrocortisone |
Placebo |
Analysis |
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Rowe et al. (2001): double-blind randomised trial |
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Dose |
Week 1: 25 micrograms daily Week 2: 50 micrograms daily Week 3 to end of week 9: 100 micrograms daily |
Dose titrated as per the intervention dose |
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Randomised |
n=50 |
n=50 |
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Efficacy |
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Primary outcome |
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Global wellness score 15-point improvement |
14% (7/50) |
10% (5/50) |
p=0.76 using ITT analysis |
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Selected secondary and additional outcomes |
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Tilt-table outcomes a |
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Analysed |
n=50 for baseline tilt test, n=33 for second tilt test during treatment |
n=50 for baseline tilt test, n=41 for second tilt test during treatment |
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Supine SBP, mmHg, mean (SD) |
Baseline: 115.8 (11.9) |
Baseline: 117.7 (13.1) |
p=0.46 |
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During treatment: 117.5 (9.6) |
During treatment: 113.7 (10.0) |
p=0.11 |
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Supine DBP, mmHg, mean (SD) |
Baseline: 72.4 (6.7) |
Baseline: 75.0 (7.2) |
p=0.06 |
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During treatment: 73.3 (6.6) |
During treatment: 73.4 (7.4) |
p=0.93 |
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HR, beats/minute Mean (SD) |
Baseline: 70.7 (8.4) |
Baseline: 69.8 (9.8) |
p=0.64 |
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During treatment: 69.0 (8.8) |
During treatment: 69.3 (9.2) |
p=0.90 |
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Number of people who had NMH provoked in stage 1 of tilt test |
Baseline: 34 |
Baseline: 33 |
p=0.83 |
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During treatment: 20 |
During treatment: 17 |
p=0.16 |
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Number of people who had NMH provoked in stage 2 of tilt test |
Baseline: 16 |
Baseline: 17 |
No p value given |
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During treatment: 6 |
During treatment: 14 |
No p value given |
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Tilt test normal in both stages |
Baseline: 0 |
Baseline: 0 |
No p values given |
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During treatment: 4 |
During treatment: 9 |
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Refused stage 2 of tilt test |
Baseline: 0 |
Baseline: 0 |
No p values given |
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During treatment: 3 |
During treatment: 1 |
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No follow-up tilt test during treatment |
5 |
1 |
No p value given |
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Safety |
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Discontinuation or withdrawal from study |
n=13 (12 people withdrew before week 5) |
n=8 (5 people withdrew before week 5) |
No statistical analysis reported |
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Participants reporting at least 1 AE |
61% |
71% |
No statistical analysis reported. |
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Mean serum sodium concentration during treatment, mEq/litre (SD) |
141.9 (2.0) |
140.3 (2.3) |
p=0.003 |
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Mean serum potassium concentration during treatment, mEq/litre (SD) |
NR |
NR |
Reported as no difference between groups, no p value given |
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Mean weight increase kg (SD) |
1.1 (1.6) |
1.2 (1.6) |
No p value given |
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Abbreviations: AE, adverse event; DBP, diastolic blood pressure; HR, heart rate; ITT, intention to treat; n, number of patients; NMH, neurally mediated hypotension; NR, not reported; SBP, systolic blood pressure; SD, standard deviation. a Tilt-table testing was performed at baseline 2 weeks before treatment started and then again during the 9th week of treatment. |
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Safety
The summary of product characteristics for Florinef (100 microgram tablets) reports that because fludrocortisone is a potent mineralocorticoid, dosage and salt intake should be monitored to avoid the development of hypertension, oedema or weight gain and that monitoring of serum electrolytes is advisable during prolonged therapy (prolonged therapy not further defined). Fludrocortisone is contraindicated for people with systemic infections (unless anti-infective therapy is used) and for people with hypersensitivity to any of the ingredients. Withdrawal after prolonged use must be gradual to avoid acute adrenal insufficiency and should involve tapering off over weeks or months depending on the treatment dose and duration. The summary of product characteristics reports that when adverse effects occur with fludrocortisone, they are usually reversible after stopping treatment and that the incidence of predictable adverse effects is dependent on the dosage, frequency and duration of treatment. The common adverse effects of systemic corticosteroids may be associated with more serious consequences in older adults.
In Campbell et al. (1975), there was an increase in mean supine SBP with fludrocortisone compared with placebo. However, in Rowe et al. (2001), mean supine SBP was similar between fludrocortisone and placebo and in Schoffer et al. (2007), mean supine SBP with fludrocortisone was similar to the mean supine SBP before treatment.
In Campbell et al. (1975), 2 people, both with known intermittent proteinuria and low plasma albumin, developed pitting ankle oedema within 1 week of starting fludrocortisone. One of these people also reported frontal headache and breathlessness. Adverse effects were said to rapidly subside after completing treatment. There was an increase in mean body weight and total plasma volume with fludrocortisone compared with placebo. There was also an increase in serum sodium concentration and a reduction in serum potassium concentration with fludrocortisone compared with placebo.
In the crossover RCT of 17 people with Parkinson's disease (Schoffer et al. 2007), there were fewer withdrawals in the fludrocortisone group (1 person) compared with domperidone (3 people). Six people reported adverse effects while receiving fludrocortisone compared with 5 people receiving domperidone. Adverse effects reported with fludrocortisone were: nausea (2 reports), with single reports of chest discomfort, morning headache, light-headedness and dizziness. No testing of statistical significance between groups was reported.
In the RCT of people with chronic fatigue syndrome (Rowe et al. 2001), study withdrawals were more common in the fludrocortisone group (13 of 50) compared with placebo (8 of 50); statistical analysis was not reported. At least 1 adverse effect was reported during treatment by 61% of people receiving fludrocortisone compared with 71% receiving placebo. No important adverse effects were reported by the study authors as lasting long after treatment discontinuation. Overall mean weight increased by 1.1 kg in the fludrocortisone group and by 1.2 kg in the placebo group. Mean serum sodium concentration was higher with fludrocortisone compared with placebo.
Longer-term safety data for fludrocortisone in treating postural hypotension are limited. One prospective observational study (Hussain et al. 1996) provided information on older adults receiving the drug over an average follow‑up of 12 months (range 2–21 months). The study included 64 people (mean age 80 years) with 1 or more hypotensive disorders. Adverse events were reported in 38 of 64 people (59.4%) and 17 stopped treatment because of adverse effects at a mean of 5 months. Reasons for drug withdrawal were: cardiac failure (n=7), systolic hypertension (n=4), depression (n=3), lack of benefit (n=2) and stroke (n=1). Hypokalaemia developed in 8 participants but there were no withdrawals for this reason. However, the observational nature of this study in a mixed population with people with 1 or more hypotensive disorders and the lack of a control arm limit the conclusions that can be drawn.
Cost effectiveness and cost
No studies on the cost effectiveness of fludrocortisone in treating postural hypotension were identified.
According to the NHS electronic drug tariff (September 2013), the cost of Florinef (100 microgram tablets; fludrocortisone acetate) is £5.05 for 100 tablets.