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Understanding Cushing’s Disease
Signs & Symptoms
Symptoms can vary greatly by patient, further complicating the path to diagnosis1
Symptoms of hypercortisolism can mimic other common conditions.1 While thin skin, easy bruising, and muscle weakness are key indicators, not all patients exhibit these features. Confirming Cushing’s disease (CD) requires additional screening, including laboratory tests, imaging, and potentially, procedures.2
CLINICAL FEATURES OF CUSHING’S SYNDROME (CS)3
Feature
Obesity or weight gain, 95%
Facial plethora, 90%
Rounded face, 90%
Decreased libido, 90%
Thin skin, 85%
Menstrual irregularity, 80%
Hypertension, 75%
Hirsutism, 75%
Depression/emotional lability, 70%
Easy bruising, 65%
Glucose intolerance, 60%
Proximal myopathy, 60%
Osteopenia or fracture, 50%
Nephrolithiasis, 50%
Some patients may have hypercortisolism despite not having these typical phenotypes.4
Comorbidities
Anxiety or depression5
Obstructive sleep apnea6
Fatigue7,8
Insomnia7,9
Unexplained osteoporosis1,10
Insulin resistance9
Carbohydrate intolerance9
Type 2 diabetes9
Hypertension1,9
Hyperlipidemia7,9
Irregular menses1
Low libido1
Normalizing cortisol levels may be an effective way to address comorbidities related to hypercortisolism.11
The signs and symptoms of CD can be confusing8:
- Signs and symptoms vary from patient to patient12
- Not all signs and symptoms are obvious and can depend on extent and persistence of disease8
- In some cases, hypercortisolism may not present classically; patients may present with only isolated symptoms4
INDICATIONS AND USAGE
ISTURISA® (osilodrostat) is indicated for the treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome for whom 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. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125 2. 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:10.1016/52213-8587(21)00235-7 3. Newell-Price J. Cushing's syndrome. Clin Med (Lond). 2008;8(2):204-208. doi:10.7861/clinmedicine.8-2-204 4. Boscaro M, Barzon L, Sonino N. The diagnosis of Cushing's syndrome: atypical presentations and laboratory shortcomings. Arch Intern Med. 2000;160(20):3045-3053. doi:10.1001/archinte.160.20.3045 5. 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 6. Kuan EC, Peng KA, Suh JD, et al. Otolaryngic manifestations of Cushing's disease. Ear Nose Throat J. 2017;96(8):28-30. doi:10.1177/014556131709600808 7. Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173(4):1-10. doi: 10.1530/EJE-15-0464 8. Boscaro M, Arnaldi G. Approach to the patient with possible Cushing's syndrome. J Clin Endocrinol Metab. 2009;94(9):3121-3131. doi:10.1210/jc.2009-0612 9. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602. doi:10.1210/jc.2003-030871 10. Braun LT, Riester A, Oßwald-Kopp A, et al. Toward a diagnostic score in Cushing's syndrome. Front Endocrinol (Lausanne). 2019;10(766):1-12. doi:10.3389/fendo.2019.00766 11. Pivonello R, De Martino MC, De Leo M, Simeoli C, Colao A. Cushing's disease: the burden of illness. Endocrine. 2017;56(1):10-18. doi:10.1007/s12020-016-0984-8 12. Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281-293. doi:10.2147/CLEP.S44336 13. Lambert JK, Goldberg L, Fayngold S, Kostadinov J, Post KD, Geer EB. Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients. J Clin Endocrinol Metab. 2013;98(3):1022-1030. doi:10.1210/jc.2012-2893 14. Braun LT, Vogel F, Zopp S, et al. Whom should we screen for Cushing syndrome? The Endocrine Society practice guideline recommendations 2008 revisited. J Clin Endocrinol Metab. 2022;107(9):e3723-e3730. doi:10.1210/clinem/dgac379