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Understanding Cushing’s Disease
Diagnosis & Treatment
Diagnosis in Cushing’s disease: A rare challenge
Cushing’s disease (CD) is often overlooked, with an average time to diagnosis of 7 years.1,2
Diagnosis begins with screening3,4
While some features are more discriminatory to indicate Cushing’s syndrome (CS), diagnosis of CD begins with screening for elevated endogenous cortisol.3-5
Steps to determine a CD diagnosis3
SCROLL TO VIEW DIAGNOSTIC STEPS
Testing options to determine a CD diagnosis
| Test | Considerations |
|---|---|
| Late-night salivary cortisol (LNSC) test | At least 2 to 3 tests recommended. Sample at regular bedtime. Not recommended in patients with abnormal day/night cycles. Confirm which type of laboratory assay to use (immunoassay or LC-MS).3 |
| 24-hour UFC | Perform at least 2 to 3 screenings. Results should take into consideration the sex, BMI, age, urinary volume, and sodium intake of the patient.3 |
|
Overnight 1-mg DST
OR |
Test at 8 AM after 1-mg dexamethasone has been administered between 11 PM and midnight.3 Should not be used in pregnant women.6 False-positive rates for the overnight DST (1 mg and 2 mg) are seen in 50% of women taking oral contraceptives.6 Normal response: serum cortisol concentration <1.8 μg/dL (50 nmol/L).3 False positives are common; measuring dexamethasone concomitantly with cortisol can reduce risk of false positives.3 |
|
OR 48-hour, 2-mg/d DST |
Administer dexamethasone 0.5 mg every 6 hours for 48 hours, beginning at 9 AM on Day 1.6 Should not be used in pregnant women.6 False-positive rates for the overnight DST (1 mg and 2 mg) are seen in 50% of women taking oral contraceptives.6 Normal response: serum cortisol concentration <1.8 μg/dL (50 nmol/L).3 False positives are common; measuring dexamethasone concomitantly with cortisol can reduce risk of false positives.3 |
| IPSS | Measures ACTH levels in the pituitary gland vs ACTH levels in the peripheral blood; the gold standard test to determine if the source of ACTH is from the pituitary gland or an ectopic source. Should be performed in a specialized center.3 |
| CRH screening | Measures response to an intravenous bolus injection of recombinant human or ovine-sequence CRH at doses of 1 μg/kg of body weight (or total dose of 100 μg).8 |
| Desmopressin test | ACTH-secreting adenomas express vasopressin 3 receptors, which produce an increase in plasma ACTH concentration after desmopressin injection. Has a high specificity for Cushing’s disease.3 |
As soon as you diagnose CD, it is critical to initiate treatment to minimize further complications9
Surgery is the first-line treatment for CD, but may not be curative3
While pituitary surgery is the recommended first-line treatment for CD, recurrence after surgery is common.3
Recurrence rates
≈25%
up to 5 years9
46%
up to 13 years10
The high incidence of CD recurrence necessitates annual clinical and biochemical follow-up, or sooner if there is clinical suspicion for recurrence3,10
Pharmacologic therapy is a potential treatment choice for patients for whom surgery is not an option or has failed to effectively normalize cortisol3
Pharmacologic therapy may be appropriate for
- Patients who have refused or are ineligible for surgery3
- Patients with persistent or recurrent CD3
- Patients undergoing radiotherapy who require further control in cortisol levels3
Persistent comorbidities despite remission could increase mortality11
INDICATION(S) AND IMPORTANT SAFETY INFORMATION
INDICATIONS AND USAGE
ISTURISA® (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
IMPORTANT SAFETY INFORMATION
Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.
Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter.
Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring.
Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.
The most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions:
- CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
- CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.
Use in Specific Populations:
- Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see the full Prescribing Information.
INDICATION(S) AND IMPORTANT SAFETY INFORMATION
INDICATIONS AND USAGE
ISTURISA® (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
IMPORTANT SAFETY INFORMATION
Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.
Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter.
Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring.
Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.
The most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions:
- CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
- CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.
Use in Specific Populations:
- Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see the full Prescribing Information.
References: 1. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi:10.1530/EJE-11-1095 2. Papoian V, Biller BMK, Webb SM, Campbell KK, Hodin RA, Phitayakorn R. Patients’ perception on clinical outcome and quality of life after a diagnosis of Cushing syndrome. Endocr Pract. 2016;22(1):51-67. doi:10.4158/EP15855.OR 3. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7 4. Newell-Price J. Cushing’s syndrome. Clin Med (Lond). 2008;8(2):204-208. doi:10.7861/clinmedicine.8-2-204 5. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;17(7):281-293. doi:10.2147/CLEP.S44336 6. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125 7. Patronas N, Bulakbasi N, Stratakis CA, et al. Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors. J Clin Endocrinol Metab. 2003;88(4):1565-1569. doi:10.1210/jc.2002-021438 8. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605-1617. doi:10.1016/S0140-6736(06)68699-6 9. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385-486. doi:10.1210/er.2013-1048 10. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358-362. doi:10.1210/jc.2007-2013 11. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet. 2015;386(9996):913-927. doi:10.1016/S0140-6736(14)61375-1