ISTURISA START FORM Prescribing Information
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Patient Resources

Cushing’s disease overview brochure
Getting Patients Started
Isturisa Patient Brochure
Symptom and self-monitoring diary

HCP Resources

R.A.R.E. HUB BROCHURE
Cushing’s Disease Informational Flashcard

FAQs

When assessing patient response to ISTURISA, can I assess their changes in signs and symptoms of Cushing’s disease instead of measuring cortisol directly?

The goal of treatment with ISTURISA is to normalize cortisol levels in patients who have persistent Cushing’s disease. As such, you should objectively measure and assess your patients’ cortisol levels. The ISTURISA Prescribing Information states that the maintenance dosage should be individualized and determined by titration based on cortisol levels as well as by patients’ signs and symptoms.1

It is also important to monitor cortisol so you can keep an eye out for hypocortisolism. If hypocortisolism occurs, you can determine whether a dose adjustment, temporary discontinuation, or other corrective steps may be necessary, such as initiating glucocorticoid replacement therapy.1

The length of time and the severity of hypercortisolism to which a patient is exposed have both been linked to higher morbidity and mortality rates in people with persistent or recurrent Cushing’s disease.2-12

By monitoring cortisol levels directly, you will be able to assess whether the treatment you’ve chosen is reducing dangerous excess cortisol.1

The ISTURISA Prescribing Information also states that once the maintenance dosage is achieved, you should monitor cortisol levels at least every 1−2 months or as indicated.1

In the LINC 3 study, why were anti-hypertensive and anti-diabetic medications and dose increases allowed during therapy with ISTURISA?

Anti-hypertensive and anti-diabetic medications and dose increases were allowed in patients who were already receiving such medications because it would have been unethical to deny those medicines to patients who needed them to help keep those conditions under control. Therefore, the individual contributions of ISTURISA or of the anti-hypertensive and anti-diabetic medication adjustments could not be clearly established in the LINC 3 study.1

Why is the diagnosis of Cushing’s disease often a long and difficult process?

Cushing’s disease is a rare hormonal disorder caused by a pituitary adenoma that secretes excess adrenocorticotropic hormone (ACTH).13-16

  • Prevalence is estimated at 40 cases per million6
  • Incidence ranges from 1.2 to 2.4 per million per year6
  • Cushing’s disease has an incidence of 10 to 15 cases per million per year in the United States17

Cushing’s disease is frequently misdiagnosed. Since the symptoms are similar to other more common diseases, those other diseases are usually suspected and treated first. It takes an average of 7 years before Cushing’s disease is diagnosed.18

Years of misdiagnosis can occur as a result of symptoms similar to other common diseases, alcoholism, morbid obesity, poorly controlled diabetes, depression or other psychiatric disorders, slow-growing tumors, and slowly progressive symptoms. Further complicating the diagnosis, the signs and symptoms may not be the same in all people.19-21

The symptoms of Cushing’s disease often mimic those of more common diseases and conditions, including:

  • Hyperglycemia19
  • Menstrual irregularities19,22
  • Hyperlipidemia19
  • Depression and mood disorders19
  • Hypertension19,22
  • Infections14
  • Obesity19,22
  • Excessive body hair growth19
  • Diabetes22
  • Kidney stones14

Diagnosis of Cushing’s disease is often an arduous process. Both Cushing’s syndrome and Cushing’s disease cause hypersecretion of cortisol, so they lead to similar symptoms.13-16

For more information on the process of diagnosing Cushing’s disease, please see the Cushing’s DISEASE DIAGNOSIS AND TREATMENT BROCHURE.

What is the starting dose of ISTURISA?

The starting dose of ISTURISA is one 2-mg tablet, taken orally twice per day, with or without food.1*

The dose should then be titrated up by 1 to 2 mg twice daily, no more frequently than every 2 weeks based on the rate of cortisol changes, individual tolerability, and improvement in signs and symptoms of Cushing’s disease. If a patient tolerates ISTURISA dosage of 10 mg twice daily and continues to have elevated 24-hour urinary free cortisol (UFC) levels above the upper limit of normal, the dosage can be titrated further by 5 mg twice daily every 2 weeks.1

You should monitor cortisol levels from at least two 24-hour UFC collections every 1–2 weeks until an adequate clinical response is maintained.1

The maintenance dosage of ISTURISA is individualized and determined by titration based on cortisol levels and patient’s signs and symptoms.1

*The recommended starting dose for patients with moderate hepatic impairment (Child-Pugh B) is 1 mg twice daily; for patients with severe hepatic impairment (Child-Pugh C), the recommended starting dose is 1 mg once daily in the evening.

What was the dosage that the majority of patients were on in the clinical studies?

The maintenance dosage in clinical trials varied between 2 mg and 7 mg twice daily in clinical trials. The maximum recommended maintenance dosage of ISTURISA is 30 mg twice daily.1

Once the maintenance dosage is achieved, you should monitor cortisol levels at least every 1−2 months or as indicated.1

How much will ISTURISA cost?

Eligible patients with commercial insurance may receive ISTURISA at a cost of no more than $20 per month.*

By choosing ISTURISA for your patients, you will be selecting a clinically proven treatment to normalize and sustain cortisol levels in a majority of patients. Through the R.A.R.E. Patient Support Program, Recordati Rare Diseases provides a broad range of support, including access and financial services to help ensure that those patients for whom you prescribe ISTURISA will receive the therapy you intend for them.

In addition to co-pay assistance for eligible patients, our specialty pharmacy partner, AnovoRx, will help facilitate financial assistance including:

  • Patient Assistance Program for those who are eligible and uninsured or underinsured
  • Sharing of information about independent organizations that may provide other forms of information and assistance

The R.A.R.E. Patient Support Program also provides significant support for trained pharmacists and a registered nurse to help monitor patients and help the patient have a positive experience.

*Eligibility requirements, restrictions, and limitations apply.

Which patients are appropriate for ISTURISA?

ISTURISA is indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Appropriate patients include those with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery.1

Patients who entered the LINC 3 clinical trial were varied in terms of their race, ethnicity, and traits as well as their disease characteristics. The mean age at enrollment was 41 years; 77% of patients were female. Overall, 96% of patients had received previous treatments for Cushing’s disease prior to entering the study, of which 88% had undergone surgery. Persistence or recurrence of Cushing’s disease was evidenced by the mean of three 24-hour urinary free cortisol (mUFC) > 1.5 x upper limit of normal (ULN). The mean UFC at baseline was 1006 nmol/24 hr, which corresponds to approximately 7 x ULN. The median UFC at baseline was 476 nmol/24 hr, which corresponds to approximately 3.5 x ULN.1 Common values for ULN are 138 nmol/24 hr, which is equivalent to 50 mcg/24 hr.

What are the common adverse events associated with ISTURISA?

The most common adverse reactions (incidence > 20%) associated with ISTURISA therapy in clinical trials were adrenal insufficiency, fatigue, nausea, headache, and edema. To review more information regarding the safety of ISTURISA, please see the full safety table and profile.1

How does ISTURISA work?

ISTURISA is a potent cortisol synthesis inhibitor that blocks the enzyme 11beta-hydroxylase to interrupt the last step of cortisol synthesis.1,12,23-25

ISTURISA is the first and only FDA-approved therapy that does this.1

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

Warnings and Precautions

  • 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. Please see section 5.1 of full Prescribing Information.

    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. Please see section 5.2 of full Prescribing Information.
  • 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. Please see section 5.3 of full Prescribing Information.

Adverse Reactions

  • 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.

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

Warnings and Precautions

  • 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. Please see section 5.1 of full Prescribing Information.

    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. Please see section 5.2 of full Prescribing Information.
  • 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. Please see section 5.3 of full Prescribing Information.

Adverse Reactions

  • 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.

References: 1. ISTURISA® (osilodrostat) [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 2. Geer EB, Shafiq I, Gordon MB, et al. Biochemical control during long-term follow-up of 230 adult patients with Cushing disease: a multicenter retrospective study. Endocr Pract. 2017;23(8):962-970. 3. Geer EB, Ayala A, Bonert V, et al. Follow-up intervals in patients with Cushing’s disease: recommendations from a panel of experienced pituitary clinicians. Pituitary. 2017;20(4):422-429. 4. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. 5. Ferriere A, Tabarin A. Cushing’s syndrome: treatment and new therapeutic approaches. Best Pract Res Clin Endocrinol Metab. 2020;101381. doi:10.1016/j.beem.2020.101381. 6. Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385-486. 7. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007;92(3):976-981. 8. 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. 9. Atkinson AB, Kennedy A, Wiggam MI, et al. Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol (Oxf). 2005;63(5):549-559. 10. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. 11. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet. 2015;386(9996):913-927. 12. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. 13. NIDDK website. Cushing’s syndrome. U.S. Department of Health and Human Services. National Institutes of Health. NIH Publication No. 08-3007 July 2008. https://www.niddk.nih.gov/-/media/36A5C0B3CDE044DFB07CBAE5E5FB378A.ashx. 14. 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. 15. Lake MG, Krook LS, Cruz SV. Pituitary adenomas: an overview. Am Fam Physician. 2013;88(5):319-327. 16. 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. 17. Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208. 18. Papoian V, Biller BMK, Webb SM, et al. Patients’ perception on clinical outcome and quality of life after a diagnosis of cushing syndrome. Endocr Pract. 2016;22(1):51-67. 19. Boscaro M, Arnaldi G. Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab. 2009;94(9):3121-3131. 20. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017;126(2):404-417. 21. Ayala A, Manzano AJ. Detection of recurrent Cushing’s disease: proposal for standardized patient monitoring following transsphenoidal surgery. J Neurooncol. 2014;119(2):235-242. 22. Nieman LK, Biller BM, 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. 23. Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014;99(4):1375-1383. 24. Menard J, Watson C, Rebello S, et al. Hormonal and electrolyte responses to the aldosterone synthase inhibitor LCI699 in sodium depleted healthy subjects. J Am Coll Cardiol. 2010;55(10):A61.E583. 25. Data on file. Recordati Rare Diseases Inc. Lebanon, NJ.