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Glucocorticoid withdrawal
Authors: Daniel E Furst, MD, Kenneth G Saag, MD, MSc
Section Editor: Eric L Matteson, MD, MPH
Deputy Editor: Monica Ramirez Curtis, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2020. | This topic last updated: Jul 12, 2019.

INTRODUCTION

Chronic glucocorticoid therapy is used in the treatment of a variety of disorders because of its potent antiinflammatory effects and, occasionally, because it is thought to have
immunosuppressive activity [1]. Among the rheumatic diseases in which glucocorticoids are often used are rheumatoid arthritis, large- and small-vessel vasculitis, systemic lupus
erythematosus, polymyalgia rheumatica, and, in some cases, the arthritis associated with inflammatory bowel disease [1].

Despite its efficacy, steroid-induced side effects generally require tapering of the drug as soon as the disease being treated is under control. Tapering must be done carefully to avoid
both recurrent activity of the underlying disease and possible cortisol deficiency resulting from hypothalamic-pituitary-adrenal axis (HPA) suppression during the period of steroid
therapy. (See "Pharmacologic use of glucocorticoids", section on 'HPA axis suppression'.)

This topic discusses the major issues related to tapering, the regimen(s) we use in most patients, and other glucocorticoid tapering regimens that have been reported in the literature.

The clinical manifestations, diagnosis, and treatment of adrenal insufficiency are presented separately. (See "Clinical manifestations of adrenal insufficiency in adults" and "Treatment
of adrenal insufficiency in adults".)

INDICATIONS FOR WITHDRAWING GLUCOCORTICOIDS

It is helpful to briefly review the indications for glucocorticoid withdrawal before discussing the different glucocorticoid withdrawal regimens. These indications include the following:

● When the maximum desired therapeutic benefit has been obtained

● When inadequate therapeutic benefit has been obtained after an adequate trial
● When side effects, such as osteoporosis or hypertension, become serious or uncontrollable with medication

In addition, there are two complications that require immediate cessation of glucocorticoids or a significant rapid reduction, rather than tapering:

● Steroid-induced acute psychosis that is unresponsive to antipsychotic medications

● Herpesvirus-induced corneal ulceration, which can rapidly lead to perforation of the cornea and possibly permanent blindness

If immediate cessation is not possible (eg, because of a critical clinical need), use of the lowest necessary dose, then discontinuing steroids as soon as possible, is strongly advised.

GLUCOCORTICOID PREPARATIONS

Prednisone will be the agent discussed, although other glucocorticoid preparations are available (table 1) (see "Pharmacologic use of glucocorticoids"). These preparations are
available in various strengths (eg, 1, 2, 5, 10, 20 mg for prednisone) and in various formulations (tablet, intravenous preparations, intramuscular preparations, and rectal
suppositories). Differences in the absorption or metabolism of these various strengths and formulations could affect the ability to taper steroids. Fortunately, most commercially
available prednisone and prednisolone preparations appear to be bioequivalent. This can be illustrated by the following observations:

● In vivo studies using healthy males in a crossover study revealed no statistical difference in any pharmacokinetic parameter with five different oral prednisone preparations [2].

● Rectal and oral absorption of methylprednisolone are equivalent, with the relative bioavailability of oral to rectal administration being 90 percent [3].

● The systemic bioavailability of prednisone is equivalent to that of prednisolone (0.77 to 0.80) [4]. Prednisone itself is biologically inactive, but it is rapidly converted to the active
form prednisolone. However, patients with severe liver disease may have difficulty converting prednisone to prednisolone; in such patients, it is possible that one might not get
the same effect from prednisone as from prednisolone. In addition, certain drug interactions can affect the metabolism and bioavailability of prednisone. As an example,
barbiturates, phenytoin, or rifampin, attenuate the biological effects of glucocorticoids (table 2).

Steroid pharmacokinetics — Tapering regimens could potentially be influenced if drug distribution changed at varying prednisone doses. Although there is a trend toward dose-
dependent kinetics, with larger doses being cleared more rapidly, the effect is relatively small and usually not of great clinical importance [5-7].

Other factors can influence pharmacokinetics. One interesting study examined 54 patients of varying ages who were given oral and intravenous methylprednisolone and
prednisolone [8]. Eleven patients (20 percent) demonstrated unusual kinetics. Their drug clearance was approximately twice that of the rest of the population without an identifiable
cause. Other findings included incomplete absorption of glucocorticoids in four patients and an inverse correlation (r = -0.88) between prednisolone clearance and age, which means
that a given dose may have a greater effect in older persons. This relation to age has been confirmed in other studies [9]. In addition, prednisolone clearance is also slower in African
Americans compared with Caucasians [10].

With this degree of interpatient variability in kinetics, it is conceivable that some patients may show greater withdrawal symptoms than others. This may occur despite the known
difference between plasma glucocorticoid kinetics and biologic activity.

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SUPPRESSION

Administration of exogenous glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis (HPA). Abrupt cessation, or too rapid withdrawal, of glucocorticoids in such patients
may cause symptoms of adrenal insufficiency. HPA suppression and the clinical manifestations of adrenal insufficiency are presented separately. (See "Pharmacologic use of
glucocorticoids", section on 'HPA axis suppression' and "Clinical manifestations of adrenal insufficiency in adults".)

Identifying patients with HPA suppression — The potency, dose, and duration of glucocorticoid use are important but imperfect predictors of the presence of HPA suppression [11].
A clinical decision about a particular patient's risk of having HPA suppression guides subsequent decision making about glucocorticoid tapering. Patients exposed to glucocorticoids
can be classified and managed as follows:

● Patients suspected of having HPA suppression who are otherwise candidates for glucocorticoid withdrawal can be cautiously tapered. (See 'Tapering regimens' below.)

● Patients determined to have a low risk of clinically significant HPA suppression may have glucocorticoids weaned as dictated by control of disease activity rather than by concern
for adrenal insufficiency.

● Patients for whom the likelihood of HPA suppression is uncertain, but for whom the consequences of developing acute adrenal insufficiency are serious (eg, the patient who is
about to undergo major surgery), may benefit from testing of the HPA functional reserve to guide further therapy.

Characteristics of patients who are likely to have HPA suppression and those who are unlikely to, or for whom the likelihood of HPA suppression is uncertain, are discussed in more
detail separately (see "Pharmacologic use of glucocorticoids", section on 'HPA axis suppression' and "The management of the surgical patient taking glucocorticoids", section on
'Evaluation of HPA axis suppression'). The following is a brief summary:

HPA suppression likely — Patients who have received glucocorticoids and who meet the following criteria are presumed to have HPA suppression:

● Anyone who has received a glucocorticoid dose comparable with more than 20 mg of prednisone a day for more than three weeks
● Anyone who has received an evening/bedtime dose of ≥5 mg of prednisone for more than a few weeks
● Any patient who has a Cushingoid appearance

Such patients do not need testing to evaluate their HPA function, but should be treated like any patient with secondary adrenal insufficiency, including the wearing of a medical alert
bracelet or necklace and carrying an emergency medical information card. We advise patients on glucocorticoids with presumed HPA suppression to seek immediate medical
attention for diagnostic and therapeutic intervention if they develop symptoms of adrenal insufficiency. It is reasonable for patients without access to nearby medical care to carry a
preloaded 1 mL syringe containing 4 mg of dexamethasone phosphate to inject in emergencies. (See "Pharmacologic use of glucocorticoids", section on 'Complications of chronic
use'.).

HPA suppression unlikely — Patients who meet one of the following criteria regarding steroid use are less likely to have a suppressed HPA and therefore may have
glucocorticoids weaned as is appropriate for the underlying disease.

● A patient who has received any dose of glucocorticoid for less than three weeks
● Patients treated with alternate-day prednisone at a dose of less than 10 mg (or its equivalent)

Intermediate/uncertain risk of HPA suppression — Patients who have an intermediate or uncertain risk of HPA suppression include those with the following characteristics:

● Those taking 10 to 20 mg of prednisone per day for more than three weeks
● Any patient who has taken any dose less than 10 mg of prednisone per day for more than a few weeks (provided that it is not taken as a single bedtime dose)

If withdrawal from glucocorticoids is otherwise indicated, gradual reduction in dose is appropriate for these patients with an intermediate or uncertain risk of HPA suppression. Such
patients do not need to be tested for HPA functional reserve unless abrupt discontinuation is being considered or the patient is facing an acute stress such as surgery. In the latter
case, one can give stress doses of glucocorticoids (table 3) or, if time permits, test for the responsiveness of the adrenal with an adrenocorticotropic hormone (ACTH [cosyntropin])
stimulation test. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)

Estimation of HPA suppression — Identifying the degree of HPA suppression is not simple clinically. Thus, in practice it is unusual to perform any testing of HPA function prior to
beginning the glucocorticoid withdrawal process. However, as noted above, in certain settings (eg, the patient for whom elective surgery is planned) such testing may be warranted.
(See "The management of the surgical patient taking glucocorticoids", section on 'Evaluation of HPA axis suppression'.)

The response to administration of synthetic ACTH is the preferred method to assess adrenocortical function. Although the cosyntropin test does not provide information about
hypothalamic function, it has the advantage that it can be performed in the office or clinic setting over the course of approximately one-hour. Test results should be available within
hours to days thereafter. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)

Low-dose ACTH stimulation test — In most patients who require testing, we use the low-dose (1 mcg) ACTH test for initial testing. The low-dose ACTH test and the criteria of a
normal adrenal response are reviewed in detail elsewhere. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test".)

Other tests either do not address the adrenal response to stress (eg, plasma cortisol or urinary cortisol excretion), are impractical due to limited drug availability (metyrapone
stimulation test), or are associated with potential risks (insulin-induced hypoglycemia test).

Recommendation — Testing for HPA-axis function is appropriate when patients are using ≤5 mg/day of prednisone and there is difficulty reducing the dose further because of non-
disease related symptoms. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test", section on 'Low-dose ACTH stimulation test'.)

OTHER FORMS OF GLUCOCORTICOID DEPENDENCE

Other forms of steroid dependence (beyond symptomatic and biochemical evidence of hypothalamic-pituitary-adrenal axis [HPA] suppression) have been identified which can hinder
steroid tapering. These include [12,13]:

● Psychologic dependence on steroids

● Recrudescence of the disease for which the drug was prescribed
● Symptoms of apparent adrenal insufficiency despite normal HPA function and lack of disease recrudescence

TAPERING REGIMENS
There is a paucity of clinical evidence to support any particular regimen of glucocorticoid tapering. Published, controlled, trial-derived data do not specifically address the issue of
weaning patients from long-term moderate or high-dose glucocorticoids in chronic rheumatic or other inflammatory disorders. The following illustrative reviews and selected studies
have principally addressed the effect of glucocorticoid tapering regimens on the activity of the underlying disease:

● A 2013 systematic review of glucocorticoid tapering regimens for rheumatoid arthritis found six randomized trials and four long-term extension trials with limited data and great
variability in the tapering regimens [14]. Glucocorticoid tapering was less successful in patients with longer disease duration. Success rates were 31 to 42 percent in patients with
6.3 and 9.3 years of disease, respectively, whereas success rates in patients with less than two years of disease duration ranged from 78 to 92 percent. Few trials described a
specific tapering regimen for glucocorticoid withdrawal. Two randomized trials recommended a variant of tapering by skipping more days between doses but keeping the dose
unchanged (eg, 7.5 mg every other day for two weeks, then every third day for two weeks, then discontinued). Another study decreased the prednisone dose by 1 mg every four
weeks at doses below 5 mg daily.

● A 2002 systematic review found nine controlled trials with random patient assignment that compared different glucocorticoid tapering regimens [15]. The published reports
reviewed dealt almost exclusively (seven of nine trials) with the treatment of asthma or chronic obstructive pulmonary disease (COPD) exacerbations and generally assessed
relapse-rates and/or physiologic measures (such as peak expiratory flow rates, forced expiratory volumes, or oxygen saturation) as patients were weaned from systemic to
inhaled glucocorticoids.

The authors of the review concluded that there was no significant difference between abrupt, rapid, or slow glucocorticoid tapering regimens for these outcomes in asthma or
COPD. The other two trials reviewed were 7- versus 15 week-tapering regimens in Crohn disease and 10- versus 21-week tapering in bone marrow transplant patients with graft
versus host disease [16,17]. Again, in these latter two studies there were no clinically significant differences in outcomes between the shorter and longer tapers.

● A trial evaluated 46 children with nephrotic syndrome who were treated with high doses of prednisolone (60 mg/m2 per day) [18]. Tapering was performed over eight weeks or
seven months. Twenty-nine children in the short-taper group received 60 mg/m2 per day for four weeks, followed by 40 mg/m2 per day on three days a week for four weeks.
Prednisolone was then discontinued. Seventeen children in the long taper group received 60 mg/m2 per day for four weeks, 60 mg/m2 per day on alternate days for four weeks,
followed by tapering by 10 mg/m2 every other day every four weeks over seven months. The number of patients who relapsed with the nephrotic syndrome within six months
after initial taper was significantly higher in the rapid taper group.

RECOMMENDED TAPERING REGIMEN

Short-term glucocorticoid therapy (up to three weeks), even if at a fairly high dose, can simply be stopped and need not be tapered. Hypothalamic-pituitary-adrenal axis (HPA)
suppression due to glucocorticoid use of this duration will not persist and is highly unlikely to have any clinical consequence. However, in a frail or dangerously ill patient, the clinician
may elect to proceed more cautiously as noted below.

In patients who have taken a glucocorticoid for a longer time, we suggest a regimen which is largely based upon experience and rests upon the following assumptions:

● Factors of age, frailty, concomitant illnesses, dangerousness and likelihood of flare of underlying illness, psychological factors, and duration of previous use of glucocorticoids are
taken into account.

● The disease is sufficiently stable so that tapering of the dose is appropriate.

● The patient has received long-term steroid therapy, not recurrent "pulses" as might be used in asthma.

● The observation that HPA suppression is uncommon at prednisone doses below 5 mg/day.

The regimen we recommend also assumes that repeated morning cortisol determinations are too expensive for routine use (see 'Other published tapering regimens' below) and that
the appropriate endpoints are the patient's signs and symptoms.

The goal of tapering is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency due to persistent HPA
suppression. We generally aim for a relatively stable decrement of 10 to 20 percent, while accommodating convenience and individual patient response. The dose is tapered by:

● 5 to 10 mg/day every one to two weeks from an initial dose above 40 mg of prednisone or equivalent per day.
● 5 mg/day every one to two weeks at prednisone doses between 40 and 20 mg/day.
● 2.5 mg/day every two to three weeks at prednisone doses between 20 and 10 mg/day.
● 1 mg/day every two to four weeks at prednisone doses between 10 and 5 mg/day.
● 0.5 mg/day every two to four weeks at prednisone doses from 5 mg/day down. This can be achieved by alternating daily doses, eg, 5 mg on day one and 4 mg on day two.

This regimen will generally prevent symptoms of cortisol deficiency. At some point, however, many patients with rheumatic diseases complain of recurrent symptoms of the underlying
disease. In this setting it may be difficult to distinguish between mild symptoms of glucocorticoid withdrawal (ie, arthralgia and myalgia or "pseudorheumatism") or recrudescence of
the underlying rheumatic disease.

If the symptoms are not major, we try to wait 7 to 10 days, and use a nonsteroidal antiinflammatory drug (NSAID) or other analgesic. Resolution of symptoms during this period of
time suggests pseudorheumatism. If the symptoms do not subside within this time frame, we increase the prednisone dose by 10 to 15 percent (to the next convenient mg tablet
regimen) and maintain that dose for two to four weeks. If the symptoms resolve, the above tapering regimen can be resumed, using two to four weeks between decrements rather
than one to two weeks.

Should this modest increase in dose not be sufficient to alleviate symptoms, we double the prednisone dose. The disease flare is allowed to subside and the taper is reinstituted at a
slower rate (eg, once monthly) or at smaller decrements (eg, one-half of the original decrement).

It should also be appreciated that incremental change is inappropriate if life-threatening flares occur (as in acute recurrence of lupus nephritis, severe hemolysis, acute polymyositis,
or vasculitis). In these settings, a return to the original, highest dose of steroids should be instituted. Tapering which is slowed in rate or decrement can be undertaken after the flare
subsides, but specific guidelines become both convoluted and impractical in the latter situations.

Alternate-day regimen — We are not aware of any evidence-based data relating to steroid tapering on an alternate-day regimen. We do, however, use the following alternate-day
approach (in which the entire dose is given on the alternate days) in some patients. After the daily regimen has reached 20 to 30 mg of prednisone per day, we decrease the alternate
day dose by 5 mg every one to two weeks until the dose is 20 to 30 mg alternating with 10 mg. We then reduce the alternate-day dose by 2.5 mg every one to two weeks until the
prednisone dose on the alternate day has fallen to zero. At that point we decrease the remaining drug in the same manner as was suggested for the daily dosing regimen.
Although this regimen is generally effective in most rheumatic diseases, patients with rheumatoid arthritis often do not tolerate alternate-day dosing.

OTHER PUBLISHED TAPERING REGIMENS

Other published glucocorticoid tapering regimens include the following:

● A report in 1976 used plasma cortisol measurements to gauge withdrawal [19]. Patients returned to the clinic at two to four week intervals for morning plasma cortisol
measurement. Tapering was done at a rate of 2.5 mg of hydrocortisone/week down to a single morning dose of 10 mg of hydrocortisone (equivalent to 2 mg of prednisone).
Steroid therapy could be discontinued when the morning plasma cortisol concentration rose to greater than 10 mcg/dL. Stress doses of steroids might be needed for infections.
This approach, however, has not gained much popularity and is generally not used.

● Another report in patients with rheumatic disease suggested either switching to alternate-day therapy or gradually lowering the daily dose [20]. To switch to an alternate-day
regimen, the dose was doubled on alternate days and then tapered as described above (see 'Alternate-day regimen' above). This regimen, however, might result in synovial and
serosal flare and symptoms on the alternate days.

SUMMARY AND RECOMMENDATIONS

● The indications for glucocorticoid withdrawal include achieving the maximum desired therapeutic benefit or inadequate benefit despite an adequate trial, and the development of
serious or uncontrollable side effects from the medication. Immediate cessation or a significant rapid reduction (in those in whom complete cessation could lead to even more
serious consequences) as soon as possible is required in patients with steroid-induced acute psychosis and those with herpesvirus-induced corneal ulceration.(See 'Indications
for withdrawing glucocorticoids' above.)

● Administration of exogenous glucocorticoids can suppress the hypothalamic-pituitary-adrenal axis (HPA). Abrupt cessation or too-rapid withdrawal of glucocorticoids in such
patients may cause symptoms of adrenal insufficiency. The potency, dose, and duration of glucocorticoid use are important but imperfect predictors of the presence of HPA
suppression. (See 'Hypothalamic-pituitary-adrenal axis suppression' above and 'Identifying patients with HPA suppression' above and "Pharmacologic use of glucocorticoids",
section on 'HPA axis suppression'.)

● The response to administration of synthetic adrenocorticotropic hormone (ACTH [cosyntropin]) is the preferred method to assess adrenocortical function. Testing for HPA-axis
function is appropriate when patients are using ≤5 mg/day of prednisone and there is difficulty reducing the dose further because of non-disease related symptoms. In most
patients who require testing, we use the low-dose (1 mcg) ACTH stimulation test for evaluation. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH
stimulation test".)

● Forms of steroid dependence other than symptomatic and biochemical evidence of HPA suppression that can hinder steroid tapering include psychologic dependence on
steroids, disease recrudescence, and symptoms of apparent adrenal insufficiency despite normal HPA function and lack of disease recrudescence. (See 'Other forms of
glucocorticoid dependence' above.)

● There is a paucity of evidence to support any particular regimen of glucocorticoid tapering. Short-term glucocorticoid therapy (up to three weeks) can usually be stopped without a
taper. In patients who have taken a glucocorticoid for a longer time, have a Cushingoid appearance, or received evening dosing, we suggest a regimen which is largely based
upon experience and considers the patient’s general health status, stability of the disease being treated, and the drug regimen that has been used. The usual endpoints are the
patient's signs and symptoms. (See 'Tapering regimens' above and 'Recommended tapering regimen' above and 'Other published tapering regimens' above.)

● The goal of tapering is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency due to persistent HPA
suppression. We generally aim for a relatively stable decrement of 5 to 10 percent every one to four weeks, while accommodating convenience and individual patient response.
(See 'Recommended tapering regimen' above.)

● There is a paucity of data regarding alternate-day tapering regimens. These are generally effective in most rheumatic diseases, but patients with rheumatoid arthritis often do not
tolerate alternate-day dosing. (See 'Alternate-day regimen' above.)

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REFERENCES

1. Kirwan JR. Systemic corticosteroids in rheumatology. In: Rheumatology, Hochberg MC, Silman AJ, Smolen JS (Eds), Mosby, St. Louis 2003. p.385.

2. Francisco GE, Honigberg IL, Stewart JT, et al. In vitro and in vivo bioequivalence of commercial prednisone tablets. Biopharm Drug Dispos 1984; 5:335.

3. Garg DC, Wagner JG, Sakmar E, et al. Rectal and oral absorption of methylprednisolone acetate. Clin Pharmacol Ther 1979; 26:232.

4. Rose JQ, Yurchak AM, Jusko WJ, Powell D. Bioavailability and disposition of prednisone and prednisolone from prednisone tablets. Biopharm Drug Dispos 1980; 1:247.

5. Legler UF, Benet LZ. Marked alterations in dose-dependent prednisolone kinetics in women taking oral contraceptives. Clin Pharmacol Ther 1986; 39:425.

6. Toothaker RD, Craig WA, Welling PG. Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sci 1982; 71:1182.

7. Pickup ME, Lowe JR, Leatham PA, et al. Dose dependent pharmacokinetics of prednisolone. Eur J Clin Pharmacol 1977; 12:213.

8. Hill MR, Szefler SJ, Ball BD, et al. Monitoring glucocorticoid therapy: a pharmacokinetic approach. Clin Pharmacol Ther 1990; 48:390.

9. Tornatore KM, Logue G, Venuto RC, Davis PJ. Pharmacokinetics of methylprednisolone in elderly and young healthy males. J Am Geriatr Soc 1994; 42:1118.

10. Tornatore KM, Biocevich DM, Reed K, et al. Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients.
Transplantation 1995; 59:729.

11. Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Semin Arthritis Rheum 2016; 46:133.
 12. Kimball CP. Psychological dependency on steroids? Ann Intern Med 1971; 75:111.

13. Dixon RB, Christy NP. On the various forms of corticosteroid withdrawal syndrome. Am J Med 1980; 68:224.

14. Volkmann ER, Rezai S, Tarp S, et al. We still don't know how to taper glucocorticoids in rheumatoid arthritis, and we can do better. J Rheumatol 2013; 40:1646.

15. Richter B, Neises G, Clar C. Glucocorticoid withdrawal schemes in chronic medical disorders. A systematic review. Endocrinol Metab Clin North Am 2002; 31:751.

16. Brignola C, De Simone G, Belloli C, et al. Steroid treatment in active Crohn's disease: a comparison between two regimens of different duration. Aliment Pharmacol Ther 1994;
8:465.

17. Hings IM, Filipovich AH, Miller WJ, et al. Prednisone therapy for acute graft-versus-host disease: short- versus long-term treatment. A prospective randomized trial.
Transplantation 1993; 56:577.

18. Ueda N, Chihara M, Kawaguchi S, et al. Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome. J Pediatr 1988;
112:122.

19. Byyny RL. Withdrawal from glucocorticoid therapy. N Engl J Med 1976; 295:30.

20. Nelson AM, Conn DL. Series on pharmacology in practice. 9. Glucocorticoids in rheumatic disease. Mayo Clin Proc 1980; 55:758.

Topic 7983 Version 11.0

GRAPHICS

Comparison of systemic corticosteroid preparations

Antiinflammatory activity relative to

Equivalent doses (mg) Duration of action (hours)
hydrocortisone*

Glucocorticoids

Short acting

Hydrocortisone (cortisol) 20 1 8 to 12

Cortisone acetate 25 0.8 8 to 12

Intermediate acting

Prednisone 5 4 12 to 36

Prednisolone 5 4 12 to 36

Methylprednisolone 4 5 12 to 36

Triamcinolone 4 5 12 to 36

Long acting

Dexamethasone 0.75 30 36 to 72

Betamethasone 0.6 30 36 to 72

Mineralocorticoids

Fludrocortisone Not used for an antiinflammatory effect ¶. The typical dose of fludrocortisone for mineralocorticoid replacement 12 to 36
is 0.1 to 0.2 mg.

The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:

When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity.
20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone.
Prednisone or prednisolone given at antiinflammatory doses ≥50 mg per day provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.

* Equivalent antiinflammatory dose shown is for oral or intravenous (IV) administration. Relative potency for intraarticular or intramuscular administration may vary considerably.
¶ The antiinflammatory potency is 10 to 15 times that of hydrocortisone; however, fludrocortisone is not used clinically as an antiinflammatory agent.

Data from:
1. Schimmer BP, Funder JW. ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex. In: Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12th ed, Brunton LL, Chabner BA, Knollmann BC (Eds),
McGraw-Hill Education 2011.
2. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013, 9:30.

Graphic 64138 Version 21.0

Examples of some drug interactions with systemic glucocorticoids* [1-3]

Interacting drug classes Examples Effect Comment

Co-administration of drugs that are inducers of CYP 3A and/or P-gp may DECREASE glucocorticoid exposure and efficacy ¶

Antiseizure Carbamazepine, fosphenytoin,
phenobarbital, phenytoin, primidone
Antimicrobials Efavirenz, etravirine, nafcillin, rifampin,
rifabutin, rifapentine
Reduced glucocorticoid effects due to increased clearance.
Maximal effect occurs approximately 2 weeks after initiating a
CYP inducer and can persist for 2 or more weeks following
discontinuation of a CYP inducer.
Dose alteration of methylprednisolone may be needed.
Prednisone and prednisolone are affected considerably less by
this interaction.
Rifampin can decrease methylprednisolone, prednisone, and
prednisolone exposure.
Efavirenz, etravirine, nafcillin, rifabutin, and rifapentine can
decrease methylprednisolone exposure but are not likely to
interact with prednisone or prednisolone.

Co-administration of drugs that are inhibitors of CYP 3A and/or P-gp may INCREASE glucocorticoid exposure and toxicity ¶

Antimicrobials Clarithromycin, telithromycin Increased glucocorticoid effects due to decreased clearance. Methylprednisolone and dexamethasone clearance may be
reduced by approximately 30 to 50%. Monitor biomarkers for
Antifungal Itraconazole, ketoconazole, posaconazole, exaggerated glucocorticoid effects. Δ Dose alteration of
voriconazole methylprednisolone and dexamethasone may be needed.

Antiviral (HIV and HCV) Atazanavir, boceprevir, darunavir, Interaction with prednisone or prednisolone appears less likely.
fosamprenavir, indinavir, lopinavir, However, in some pharmacokinetic studies, increased
nelfinavir, ritonavir, saquinavir, telaprevir glucocorticoid exposure was observed. Monitoring for increased
glucocorticoid effects is suggested. Δ

Estrogens Estrogen-containing oral contraceptives, Estrogens can significantly increase glucocorticoid exposure and Monitor biomarkers for exaggerated glucocorticoid effects. Δ Dose
conjugated estrogens, esterified effects. This may be due to alteration of steroid metabolism and alteration of glucocorticoid may be needed.
estrogens, others protein binding.

Immunosuppressant Cyclosporine, tacrolimus, everolimus Increased exposure to methylprednisolone, prednisone, and Monitor biomarkers for exaggerated glucocorticoid effects. Δ Dose
prednisolone. Altered (increased or decreased) cyclosporine alteration may be needed.
concentrations and decreased everolimus concentrations with Monitor immunosuppressant concentrations closely. If possible,
dexamethasone. avoid dexamethasone with everolimus.

Multiple effects or additive toxicities

Anticoagulant, oral Warfarin Glucocorticoids may increase anticoagulant effect of warfarin. Most patients stabilized on warfarin will require a significant
alteration in warfarin dose within 3 to 7 days after initiating
glucocorticoid. Monitor INR closely to determine need for dose
adjustment.

Diuretics Furosemide, hydrochlorothiazide, others Glucocorticoids may potentiate potassium wasting effect. Evaluate serum potassium levels to determine whether alteration
of diuretic therapy and/or potassium supplementation is needed.

Fluoroquinolone Ciprofloxacin, gemifloxacin, levofloxacin, Increased risk of tendinopathy. Monitor for new-onset tendon and/or joint pain. Use combination
moxifloxacin, ofloxacin, sparfloxacin, cautiously in older adults and children.
others

Hypoglycemic Acarbose, glipizide, glyburide, insulins, Glucose dysregulation. Closely monitor blood glucose in patients at risk for glycemic
metformin, pioglitazone, sitagliptin, others dysregulation. Adjust therapy as needed.

NSAIDs Ibuprofen, indomethacin, ketorolac, Increased risk of peptic ulcer disease. Refer to UpToDate topics on major side effects of systemic
ketoprofen, naproxen, others glucocorticoids.

This table does not show all possible interactions. For additional interactions refer to appropriate UpToDate clinical topics and Lexicomp drug interactions program included with UpToDate.

CYP 3A: cytochrome P450 3A; P-gp: P-glycoprotein efflux membrane transporters; HCV: hepatitis C virus; INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs.
* The classification of effects on drug metabolism are based upon US Food and Drug Administration (FDA) guidance. [4,5] Other sources may use a different classification system resulting in some agents being classified differently.
Weak inhibitor effects are not listed. Clinically significant interactions can occasionally occur due to weak inhibitors, particularly if the target drug has a narrow therapeutic margin. Refer to the Lexicomp drug interactions program

for a full review of potential interactions.

¶ For a list of CYP 3A inducers/inhibitors (which include CYP 3A4 metabolism effects), refer to UpToDate content including a separate table that lists cytochrome P450 3A inhibitors and inducers.
Δ Biomarkers of glucocorticoid toxicity may include neuropsychiatric reactions, fluid and electrolyte disturbances, hypertension, and/or hyperglycemia.

References:
1. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 2005; 44:61.
2. Lexicomp Online. Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
3. Clinical Manual of Drug Interaction Principles for Medical Practice, Wynn GH, Oesterhelf JR, Cozza KL, Armstrong SC (Eds), APA Publishing, Washington DC 2019.
4. US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry, January 2020. Available at:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (Accessed on June 5, 2020).
5. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers (Accessed on February 11, 2020).

Graphic 53228 Version 16.0

 Corticosteroid coverage for surgery in patients taking exogenous corticosteroids

For minor procedures or surgery under local anesthesia (eg, inguinal hernia repair), take usual morning steroid dose. No extra supplementation is necessary.

For moderate surgical stress (eg, lower extremity revascularization, total joint replacement), take usual morning steroid dose. Give 50 mg hydrocortisone intravenously just before the procedure and 25 mg of hydrocortisone
every eight hours for 24 hours. Resume usual dose thereafter.

For major surgical stress (eg, esophagogastrectomy, total proctocolectomy, open heart surgery), take usual morning steroid dose. Give 100 mg of intravenous hydrocortisone before induction of anesthesia and 50 mg
every eight hours for 24 hours. Taper dose by half per day to maintenance level.

Graphic 69479 Version 5.0

Contributor Disclosures
Daniel E Furst, MD Grant/Research/Clinical Trial Support: Actelion [SSC, PAH]; Galapagos; NIH; GSK; Sanofi; Corbus; Pfizer [SSc]; Novartis [RA]; Amgen [RA, PsA]; BMS; Roche/Genentech [RA,
SSc]. Consultant/Advisory Board: Corbus; Galapagos; Novartis [SSc]; Amgen [RA, PsA]. Kenneth G Saag, MD, MSc Grant/Research/Clinical Trial Support: Amgen [Osteoporosis]; Takeda; Horizon;
SOBI; Shanton [Gout]. Consultant/Advisory Boards: AbbVie; Bayer [Rheumatoid arthritis]; Gilead; Radius; Daiichi Sankyo [Osteoporosis]; Teijin; Takeda; Horizon; SOBI; Mallinckrodt [Gout]; Amgen;
Roche-Genentech [Osteoporosis, rheumatoid arthritis]. Eric L Matteson, MD, MPH Grant/Research/Clinical Trial Support: Sun Pharmaceutical Industries, Ltd [Basic science investigation concentrating
on rheumatoid lung disease]. Consultant/Advisory Boards: Boehringer-Ingelheim [Interstitial lung disease]; Gilead Sciences [Rheumatoid arthritis]; TympoBio [Autoimmune hearing loss]; Arena
Pharmaceuticals [Autoimmune Diseases]. Speaker's Bureau: Practice Point Communications [Treatment of rheumatoid arthritis]. Other Financial Interest: SAB Biotherapeutics, Inc – Data and Safety
Monitoring Board [Infectious diseases/viral neutralizing antibodies]. Monica Ramirez Curtis, MD, MPH Nothing to disclose

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