Hypokalemia

Hypokalemia is a frequent manifestation of CS [21, 22] due to excess cortisol saturating the oxidative capacity of 11βHSD2 to inactivate cortisol to cortisone. The excess available cortisol can then act on the MR, leading to MR activation [23]. GR antagonism with mifepristone may lead to further increases in cortisol, particularly in patients with CD, which may potentially exacerbate hypokalemia. In SEISMIC, 44% of patients developed hypokalemia during mifepristone treatment [5]. Hypokalemia should be corrected prior to initiating treatment with mifepristone and potassium levels should be regularly monitored during treatment and dose escalation (Fig. 2) [16].

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Fig. 2

Suggested potassium monitoring and spironolactone dosing algorithm for potassium. ^aNote that all patients may not need proactive spironolactone. For instance, some patients, particularly those with adrenal disease may not experience substantial increases in cortisol (and associated MR activation) during mifepristone treatment. ^bMR activation with mifepristone may take several days to occur. Direct patient to call clinician’s office to report when the MR antagonist is started to facilitate appropriate follow-up. If spironolactone is not tolerated, consider an alternative MR antagonist, such as eplerenone. ^cCheck for signs of excess MR activation (e.g., edema, elevated blood pressure). Abbreviations: eGFR estimated glomerular filtration rate, MR mineralocorticoid receptor

In addition to checking a baseline potassium level before starting mifepristone, renal function assessment (estimated glomerular filtration rate [eGFR]) and medication review are also advised to identify medications that may alter potassium levels and eGFR (e.g., angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], loop diuretics, thiazides). For patients on loop or thiazide diuretics, depending on the indication (heart failure or hypertension), the clinician might consider dose adjustment or alternate therapies. Performing a dietary review with the patient and providing recommendations for a low-sodium diet, such as Dietary Approaches to Stop Hypertension (DASH), may also be beneficial [24].

To help further mitigate the risk of developing hypokalemia, a pre-treatment potassium level of at least 4.0mEq/L is recommended. If pre-mifepristone potassium is <4.0mEq/L, we recommend preemptive supplementary potassium prior to initiating mifepristone treatment. Furthermore, we recommend consideration of concomitant treatment with spironolactone. If spironolactone is not tolerated, then the alternative MR antagonist, eplerenone, may be used. See Fig. ​Fig.22 for suggested spironolactone dosing recommendations. Additional dose modifications may be made based on clinical judgment. In SEISMIC, 28% (14/50) of patients received spironolactone at doses up to 400mg daily [5].

Endometrial thickening and vaginal bleeding

Mifepristone is classified as a selective progesterone receptor modulator as well as a competitive GR antagonist. Because of PR modulation, mifepristone can cause endometrial thickening and vaginal bleeding [25, 26]. Among women with available data from SEISMIC, 38% (10/26) experienced endometrial thickening, as detected by transvaginal ultrasound [5, 16]. Although reported primarily among premenopausal women [5], cases of vaginal bleeding with mifepristone have also been reported among postmenopausal women [27]. Therefore, all non-hysterectomized women should be counseled on the risk of potential vaginal bleeding.

Providers should involve gynecology in the management and monitoring of endometrial effects of mifepristone, especially if a transvaginal ultrasound is performed [11]. The endometrial changes associated with PR modulators such as mifepristone are unique and are not indicative of hyperplasia, dysplasia, or malignancy [25, 26, 28]. We recommend that endometrial biopsies be read by pathologists familiar with the endometrial changes associated with PR modulators, to prevent potential misclassification [29, 30]. In the event of bleeding, systemic hormone treatment with progesterone will not be beneficial during mifepristone treatment. For some patients with endometrial thickening, a periodic planned mifepristone holiday, combined with a course of medroxyprogesterone to induce decidual bleeding, may be appropriate [31]. Afterwards, mifepristone may be restarted at the previous maintenance dose. Other options for vaginal bleeding management include dilation and curettage, endometrial ablation, and elective hysterectomy. Implications for future fertility should be discussed with premenopausal patients treated long-term with mifepristone. To our knowledge, there are no available studies on the use of a local intrauterine device to help prevent associated bleeding.

Thyroid function

Mifepristone use can alter thyroid function [5, 32]. In the SEISMIC trial, 19% (8/42) of patients had reversible increases in thyroid-stimulating hormone (TSH) [5]. TSH increases accompanied by reductions in serum thyroxine (T4) have also been observed within 3 months of long-term mifepristone treatment (up to 40 months) [33]. The mechanisms behind the effects of mifepristone on thyroid function are not yet fully understood and likely differ in patients with primary hypothyroidism versus secondary (central) hypothyroidism. Effects may include increased TSH secretion secondary to hypothalamic and pituitary GR inhibition rather than, or in addition to, reduced thyroid hormone secretion [33]. Pre-existing autoimmune thyroid disease and hypothyroid symptoms may be masked by hypercortisolism [18] and unmasked by mifepristone treatment [18]. If possible, all patients should undergo baseline thyroid function testing before mifepristone is initiated. Regardless of whether a patient is on thyroid medication at baseline, we recommend monitoring TSH and free T4 during mifepristone titration, every 3months during treatment, and if any signs or symptoms consistent with abnormal thyroid function develop. Monitoring total or free tri-iodothyronine (T3) levels in selected patients may also be of value. Additional monitoring and treatment recommendations are provided in Fig. 3 [34, 35]. Patients with central hypothyroidism may need substantial increases in their thyroid hormone requirement during mifepristone treatment [32]. In a small case series of patients with Cushing disease and central hypothyroidism, patients required a median levothyroxine dose increase 1.83 times the initial dose to achieve normal levels of free T4 [32]. Potential areas for future investigations include further elucidation of the effects of mifepristone on TSH secretion, T4 to T3 conversion, and thyroid-binding globulin levels.

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Fig. 3

Thyroid assessment recommendations during mifepristone treatment [34, 35]. Abbreviations: AACE American Association of Clinical Endocrinologists, ATA American Thyroid Association, BMJ British Medical Journal, MAGIC MAGIC (Making Grade the Irresistible Choice) Foundation, T3 tri-iodothyronine, T4 thyroxine, TSH thyroid-stimulating hormone

Antihypertensives

Mifepristone treatment may be associated with either a decrease in blood pressure due to inhibition of the effects of hypercortisolism or an increase in blood pressure due to cortisol-mediated MR activation [5]. Therefore, we do not consider it necessary to prophylactically reduce or discontinue antihypertensive medications before starting mifepristone provided patients are closely monitored. In general, when a patient is hypertensive at baseline, their blood pressure control should be optimized prior to starting mifepristone (spironolactone recommended as first-line option). An individualized approach to adjusting other antihypertensives may be needed, with particular attention to antihypertensives that can affect serum potassium levels (ARBs, ACE inhibitors, loop diuretics, thiazides). Monotherapeutic agents are preferred over combination formulations. Other antihypertensives (e.g., beta-blockers, alpha-blockers, calcium channel–blockers) may be indicated based on patient history.

Counsel patients to measure their blood pressure using a home blood pressure monitor during mifepristone treatment and report their results. Patients should be instructed to contact the office in the event of significant blood pressure changes or the development or worsening of peripheral edema. Consider discussing CS medication treatment with co-managing clinicians (e.g., PCP, cardiologist, nephrologist).

Anticoagulants

Mifepristone increases the concentration of warfarin. Refer to Table ​Table22 for specific recommendations for monitoring and dosing warfarin when using mifepristone. The direct oral anticoagulant (DOAC) apixaban [37] may be used with mifepristone, but caution is required due to the potential for drug-drug interaction. Rivaroxaban [38] would not be a suitable DOAC because it is metabolized primarily by CYP3A (Table 3) [12]. All patients receiving anticoagulants should be counseled on the signs of bleeding and closely monitored.

Table 3

Commonly encountered drug-drug interactions with mifepristone

Drug	Interactiona	Impacta	Recommended approacha
HMG-CoA reductase inhibitors
Simvastatin	CYP3A4 metabolism	Increased serum concentration of statins, resulting in increased side effects	Contraindicated – switch to rosuvastatin or pravastatin
Lovastatin	CYP3A4 metabolism		Contraindicated – switch to rosuvastatin or pravastatin
Atorvastatin	CYP3A4 metabolism (lesser extent)		Switch to rosuvastatin or pravastatin OR lower dose (no more than 20mg)
Fluvastatin	CYP3A4 metabolism (lesser extent)		Switch to rosuvastatin or pravastatin OR lower dose (no more than 20mg)
Opioids
Hydrocodone/APAP	CYP3A4 metabolism	Increased serum concentrations of opioids, increasing side effects	Use lowest effective dose and monitor for side effects
Oxycodone
Tramadol
Methadone	CYP3A4 metabolism and QT prolongation risk	Increased serum concentrations of methadone, increasing side effects, and risk of life-threatening QT prolongation	Use lowest effective dose and monitor for side effects and EKG changes regularly. Switch to alternative opioid if possible.
Fentanyl	CYP3A4 metabolism	Increased serum concentrations of fentanyl, leading to serious, life-threatening respiratory depression	Contraindicated – switch to alternative opioid
Anticoagulants
Warfarin	CYP2C9 metabolism (major) and CYP3A (minor)	Increased risk of bleeding and elevated INR	Increase frequency of INR monitoring. Use lowest effective dose (consider 50% reduction). Monitor after starting mifepristone and with dose titrations.
Rivaroxaban	CYP3A4 metabolism	Increased risk of bleeding	Not recommended
Apixaban	CYP3A4 metabolism (major) and CYP2C9 (minor)	Increased risk of bleeding	Reduce dose of apixaban per prescribing information [37]; monitor for bleeding events
Antibiotics
Azithromycin	QT prolongationb	Risk of QT prolongation	Hold mifepristone temporarily while treating infection
Ciprofloxacin
Levofloxacin
Moxifloxacin
Sulfamethoxazole/Trimethoprim
Benzodiazepines
Alprazolam	CYP3A4 metabolism	Increased serum concentrations of benzodiazepines, increasing side effects	Depending on indication, preferred agents would be lorazepam or oxazepam for anxiety and temazepam for sleep
Clonazepam
Diazepam
Triazolam
Flurazepam
Second generation (atypical) antipsychotics
Quetiapine	CYP3A4 metabolism (major) and QT prolongationa	Increased serum concentrations of antipsychotic, increasing side effects and risk of QT prolongation	Reduce dose and monitor patient and EKG
Risperidone
Aripiprazole
Lurasidone	CYP3A4 metabolism (major)	Increased serum concentrations, increasing side effects of lurasidone	Contraindicated with strong CYP3A inhibitors per prescribing information
Anticonvulsants
Phenobarbital	Induce CYP3A4 metabolism (strong)	Decreased serum concentrations of mifepristone	Monitor for clinical endpoints and patient’s improvement. Monitor for changes in seizure activity.
Phenytoin
Carbamazepine
Oxcarbazepine	Induces CYP3A4 (weak)
Miscellaneous
Diltiazem	CYP3A4 metabolism	Increased serum concentrations of mifepristone, diltiazem, and verapamil	Limit doses of both drugs. Start mifepristone at low doses and perform small and careful dose escalations.
Verapamil
Repaglinide	CYP2C8/2C9	Increased serum concentrations of repaglinide, increasing side effects	Reduce dose or use smallest recommended dose. Monitor blood glucose levels more frequently, especially postprandial levels.
Non-steroidal anti-inflammatory drugs (NSAIDs)	CYP2C8/2C9	Increased serum concentrations of NSAIDs, increasing side effects	Avoid if possible or use smallest recommended dose and monitor for side effects

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^aApplies to all listed drugs in class unless otherwise noted. ^bFor other potential interactions with drugs that prolong the QT interval, check online resources, such as https://crediblemeds.org/index.php/drugsearch

Abbreviations: APAP acetaminophen, CYP cytochrome P450, EKG electrocardiogram

Antidiabetes medications

Mifepristone will increase the risk of hypoglycemia when used in combination with insulins, sulfonylureas, or meglitinides. Patients receiving these antidiabetes medications will need frequent monitoring, and the medications may need to be reduced or discontinued during mifepristone initiation and treatment. Clinicians should expect insulin resistance to improve with mifepristone treatment [5, 9]. Decreased appetite, increased satiety, or nausea during mifepristone treatment may also lower insulin requirements. Extreme caution is necessary when managing patients on premixed insulins or concentrated insulins, such as U-500. See Table ​Table22 for specific proactive insulin dose-adjustment strategies.

When counseling patients, it is essential to emphasize the importance of self-monitoring blood glucose and instruct patients how to down-titrate insulin to avoid hypoglycemia (i.e., reducing or eliminating bolus insulin if limiting caloric intake or skipping meals). The use of continuous blood glucose monitoring devices should also be considered as a method of monitoring glycemic excursions while on mifepristone.

Consider reducing the doses of sulfonylureas and meglitinides by 50% or stopping these medications when mifepristone is started. Other noninsulin antihyperglycemic agents may typically be used with mifepristone with some specific cautions (see Table ​Table22).

Non–hypercortisolemic-related surgery and emergency surgery

If mifepristone is held prior to non–hypercortisolemic-related surgery, the MR antagonist may also need to be held. The half-lives of spironolactone and its active metabolites range from 1.4 to 16.5h [41]. Because of the shorter half-life of spironolactone compared with mifepristone (up to 85h), spironolactone should be continued until 2–3days before surgery. If necessary, for patients in an emergency surgical situation, discontinue mifepristone and administer dexamethasone. We recommend a conservative approach to dexamethasone dosing, using 2mg daily (intravenously or by mouth) for every 300mg of mifepristone previously administered [11]. Monitor for signs and symptoms of excess GR antagonism (see Fig. ​Fig.1),1), as previously discussed. Mifepristone may be restarted 1week postoperatively, once the patient has normal oral intake, no significant gastrointestinal complaints, and is no longer at risk for postoperative bleeding. Restart mifepristone at the presurgical maintenance dose if tolerated.

Bridge therapy

Mifepristone has been used as a temporary “bridge” therapy in patients receiving pituitary radiotherapy [42] and as pre-treatment in high-risk patients to reduce perioperative risk and improve postoperative outcomes, such as eliminating or reducing the length of postoperative adrenal insufficiency in some patients [43–47].

Monitoring serum cortisol and ACTH levels over time may be helpful in patients treated with pituitary radiotherapy who are also receiving mifepristone bridge therapy in order to detect the onset of radiotherapy treatment effect, as levels would begin to decrease. Patients must also be monitored for signs and symptoms of AI.

Perioperative management protocols for ACTH-dependent disease vary widely amongst centers and usually include measurements of postoperative ACTH and cortisol levels as indicators of treatment success and risk of relapse. These protocols may need to be modified when managing patients pretreated with mifepristone since mifepristone indirectly increases ACTH secretion from healthy pituitary corticotroph cells. Mifepristone may also be used to control disease following failed surgical procedures while other treatment options are considered.

Patients with unilateral primary adrenal hypercortisolism can also be treated with mifepristone prior to adrenalectomy. Mifepristone affects the hypothalamic-pituitary-adrenal (HPA) axis by antagonizing cortisol activity, which reduces negative feedback at the hypothalamus and corticotrophs, leading to increased ACTH secretion [5, 44, 48]. In patients with unilateral primary adrenal hypercortisolism, the rise in ACTH indicates recovery of previously suppressed corticotrophs [44]. Up to 6months of pre-treatment with mifepristone may be required to achieve this effect. The increase in ACTH in turn decreases the suppression of cortisol secretion from the contralateral adrenal gland before unilateral adrenalectomy, thereby preventing adrenal atrophy and postoperative AI. This has been shown in a clinical case report [44], where increases in ACTH, accompanied by increases in cortisol and dehydroepiandrosterone sulfate, were monitored as markers of HPA axis reactivation during mifepristone pre-treatment. Additional studies are needed to examine the benefit of GR antagonists as pre-treatment in patients with unilateral adrenal hypercortisolism.

Infection/sick days

We recommend assessing the patient for signs and symptoms of excess GR antagonism. If no acute signs or symptoms are present, the patient does not likely require supplemental dexamethasone. Clinical judgement is required. Maintain communication with the patient and exercise caution when prescribing antibiotics to prevent any potential drug-drug interactions (see Table ​Table33).

Exogenous glucocorticoid use

Mifepristone treatment is not appropriate for patients requiring high-dose exogenous glucocorticoid therapies for other underlying conditions. Mifepristone will inhibit the efficacy of these glucocorticoid therapies. Consider switching patients with asthma or chronic obstructive pulmonary disease from glucocorticoid inhalers to long-acting beta-adrenergic or long-acting anticholinergic inhalers. Patients with chronic musculoskeletal pain may experience increased pain when treated with mifepristone due to GR antagonism and may require intensified pain management. If pain medication is needed, check for drug-drug interactions. Consultation with a pain specialist or rheumatologist may be helpful. If a patient on mifepristone subsequently requires exogenous glucocorticoids for comorbidities, for example following a hospital admission, we suggest reevaluating the appropriateness of mifepristone therapy.

Special populations

In the SEISMIC study, adult patients up to 71years of age were treated with mifepristone [5]. We recommend the following considerations for the use of mifepristone in older patients (>65years):

• Older patients may be prone to develop mild hypovolemia; monitor volume status and GFR, particularly when adding an MR antagonist

• Older patients often receive polypharmacy; monitor for potential drug-drug interactions

• Slower titration may help improve tolerability

Reports of mifepristone use in pediatric patients with CS are limited [31, 49, 50]. In one report, a 16-year-old girl with Cushing disease was treated with mifepristone for 8years after multiple interventions failed, including transsphenoidal surgery and pituitary radiation [31]. During treatment, she developed endometrial hypertrophy and was given a 2-month mifepristone holiday every 4–6months, together with a course of medroxyprogesterone to induce decidual bleeding.

Some patients with nonalcoholic fatty liver disease (NAFLD) have shown subtle, chronic dysregulation of the HPA axis that correlates with the severity of liver histopathology, suggesting that hypercortisolism may be implicated in the development of NAFLD [51]. Limited data have shown improvement in liver enzymes in patients with NAFLD treated with mifepristone [52]. Further studies are needed regarding the effectiveness of mifepristone in patients with co-existing fatty liver disease.

The authors thank Sarah Mizne, PharmD, and Don Fallon, ELS, of MedVal Scientific Information Services, LLC (Princeton, NJ) for medical writing and editorial assistance, which were funded by Corcept Therapeutics. The authors also thank Behn Sarafpour, PharmD; Michele Lamerson, RN, MS, CPNP; Rebecca Ray, APRN, FNP-C; and Dat Nguyen, PharmD, of Corcept Therapeutics for valuable scientific support in preparation of the consensus meeting and discussions.