WHY ISTURISA

Safety

ISTURISA safety was assessed in two Phase 3 clinical studies.1,2
Select a study to review adverse reactions.

Linc 3
Linc 4

LINC 3 study safety profile demonstrated through 48 weeks3

Adverse reactions among 137 patients with Cushing's disease who received at least one dose of ISTURISA in the study3

Adverse reaction (Frequency > 10%)
Adrenal insufficiencya 43.1
Fatigueb 38.7
Nausea 37.2
Headachec 30.7
Edemad 21.2
Nasopharyngitis 19.7
Vomiting 19.0
Arthralgia 17.5
Back pain 15.3
Rashe 15.3

Adrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, cortisol decreased. One-third of the subjects with this event had low cortisol levels indicative of adrenal insufficiency. The majority of subjects had normal cortisol levels suggesting a cortisol withdrawal syndrome.

Fatigue includes lethargy, asthenia.

Headache includes head discomfort.

Edema includes edema peripheral, generalized edema, localized edema.

Rash includes rash erythematous, rash generalized, rash maculopapular, rash papular.

  • Among the 43% of patients who were deemed to have experienced adrenal insufficiency, 1/3 had low cortisol levels indicative of adrenal insufficiency3,a
  • Hypocortisolism was reported at a rate of 31% during weeks 1 to 12 and 18% during weeks 12 to 263
    • Majority of cases were manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy3
    • 25 of 70 (36%) patients with one or more hypocortisolism-related event received glucocorticoid supplementation during the duration of the study1

Hirsutism was observed in 12% (13/106) of female patients.1,3 This adverse event was considered mild to moderate,f and no patient discontinued as a result.1

Mild to moderate = severity rated by investigator as 1 or 2 in the LINC 3 clinical trial.4

Learn about the efficacy of ISTURISA from the LINC 3 clinical trial

References: 1. Pivonello R, Fleseriu M, Newell-Price J, et al; LINC 3 investigators. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0 2. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882-e2895. 3. Isturisa. Package insert. Recordati Rare Diseases Inc; 2025. 4. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9)(suppl). doi:10.1016/S2213-8587(20)30240-0

The most common adverse reactions observed during the 12-week placebo controlled period study while on ISTURISA2

Adverse reaction ISTURISA
(Frequency ≥ 10%)(N=48) 		Placebo (N=25)
Decreased appetite 38 16
Arthralgia 35 12
Nausea 31 12
Fatiguea 29 16
Myalgiab 23 4
Diarrhea 21 0
Dizziness 19 16
Adrenal insufficiency 15 0
Tachycardiac 15 0
Nasopharyngitisd 15 4
Hypotensione 15 0
Pruritus 13 0
Abdominal painf 13 4
Renal and urinary tract infectiong 13 0
Peripheral edemah 10 4
Viral infectioni 10 0
Vomiting 10 0
Blood testosterone increased 10 0

Some patients may experience adrenal insufficiency with ISTURISA3,a

  • Adverse reactions potentially related to hypocortisolism were observed at a rate of 15% (7/48) up to week 12 in the LINC 4 study2

Fatigue includes asthenia, fatigue, and malaise

Myalgia includes myalgia and fibromyalgia

Tachycardia includes tachycardia and sinus tachycardia

Nasopharyngitis includes upper respiratory tract infection, nasopharyngitis, and pharyngitis

Hypotension includes hypotension and orthostatic hypotension

Abdominal pain includes abdominal pain, abdominal pain upper, and gastrointestinal pain

Renal and urinary tract infection includes urinary tract infection and cystitis

Peripheral edema includes edema peripheral and peripheral swelling

Viral infection includes Influenza, conjunctivitis viral, Dengue fever, and oral herpes

Some patients may experience signs of adrenal insufficiency,a which can be managed with patient-specific titration or temporary discontinuation3

Percentage of hypocortisolism-related events in each study

LINC 33

43%

of patients in the LINC 3 study3

Patients in LINC 3 received dose increases every 2 weeks.1

LINC 42

27%

of patients in the LINC 4 study2

Patients in LINC 4 received dose increases approximately every 3 weeks.2

Among the 43% of patients who were deemed to have experienced adrenal insufficiency, 1/3 had low cortisol levels indicative of adrenal insufficiency.3,a

ISTURISA titration was slower in LINC 4 and did not compromise its ability to normalize cortisol in patients with CD. In LINC 4, decisions to increase dose took into consideration all data for each patient, including mUFC level, rate of decrease of mUFC, and tolerability of ISTURISA.2,5

Patients should be monitored regularly and educated on the symptoms of adrenal insufficiency, such as nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness, to allow prompt management. Adrenal insufficiency can be managed through dosage reduction or interruption.3

Adrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, and cortisol decreased.3

CD, Cushing’s disease; mUFC, mean urinary free cortisol.

“Cushing’s patients should initiate osilodrostat at a low dose (2 mg twice daily), with incremental dose increases based on disease severity and individual response/tolerability aimed at normalizing cortisol levels.”4

Fleseriu et al, Endocrine Practice

Chat bubbles Icon

Counsel patients to recognize and report the symptoms suggestive of hypocortisolism3

Nausea
Fatigue
Loss of appetite
Low blood pressure
Vomiting
Abdominal pain
Dizziness
Syncope
Learn about the efficacy of ISTURISA from the LINC 4 clinical trial

References: 1. Pivonello R, Fleseriu M, Newell-Price J, et al; LINC 3 investigators. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0 2. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882-e2895. 3. Isturisa. Package insert. Recordati Rare Diseases Inc; 2025. 4. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-875. doi: 10.1016/S2213-8587(21)00235-7 5. Fleseriu M, Auchus RJ, Snyder PJ, et al. Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing’s disease (CD): results from two phase III trials (LINC3 and LINC4). Endocr Pract. 2021;27(suppl 6):S112. Abstract #999926. doi:10.1016/j.eprac.2021.04.707

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 interruption or 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, edema, decreased appetite, arthralgia, myalgia, and diarrhea.

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:

Use in Specific Populations:

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 full Prescribing Information.

Patient portrayal.

Meghan, Actor Portrayal
BASELINE CHARACTERISTICS Age: 34 Race: White Height: 5'6" Weight: 80.1 kg (177 lb) BMI: 28.6 kg/m2
Diagnosis Cushing’s disease: recurrent
Time since diagnosis  6 years
Treatment
  • Transsphenoidal surgery was performed within 2 months of diagnosis 
  • Pituitary radiotherapy was performed 2 years ago
Status
  • In remission, but beginning to develop symptoms of recurrence
Symptoms
  • Weight gain in the abdomen
  • Fatigue and sleep disturbances
  • Anxiety and depression
  • Easy bruising
  • Increased thirst and urination
Comorbidities
  • Depression/anxiety
  • Hyperlipidemia
  • Prediabetes
Vital signs and labs Blood pressure: 124/86 mm Hg HR: 72 bpm Total cholesterol: 213 mg/dL (reference range: <200 mg/dL) LDL: 112 mg/dL (reference range: <100 mg/dL) HDL: 45 mg/dL (reference range: >60 mg/dL) Glucose: 123 mg/dL (reference range: <100 mg/dL) HbA1c: 6.2% (reference range: <5.7%) UFC: 217.5 nmol/24 h (78.8 μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 1.5 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  2. How do you evaluate severity of disease in your patients?
  3. What are your treatment goals for this patient?
  4. What do you consider to be the appropriate next therapy option for this patient?
  5. Would you consider ISTURISA an appropriate option for this patient? Why or why not?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient

Patient portrayal.

Mike, Actor Portrayal
BASELINE CHARACTERISTICS Age: 34 Race: White Height: 5'10” Weight: 95.9 kg (211 lb) BMI: 30.3 kg/m2
Diagnosis Cushing’s syndrome: treatment naive
Time since diagnosis 7 months
Treatment
  • Exogenous sources of hypercortisolemia were ruled out
  • Standard imaging techniques were unsuccessful in locating the tumor
  • Inferior petrosal sinus sampling indicated an ectopic source
  • Patient is not a candidate for surgical intervention
Status
  • Further imaging investigation is required
  • Patient is experiencing symptoms of hypercortisolemia that may benefit from medication therapy
  • Cardiometabolic parameters are currently not controlled despite lifestyle changes and maximized treatment
Symptoms
  • Weight gain in the abdomen
  • Rounded face
  • Hypertension
  • Diabetes
  • Daytime fatigue and nighttime insomnia
  • Muscle weakness
Comorbidities
  • Hypertension
  • Diabetes
  • Hyperlipidemia
Vital signs and labs Blood pressure: 146/92 mm Hg HR: 68 bpm Total cholesterol: 238 mg/dL (reference range: <200 mg/dL) LDL: 121 mg/dL (reference range: <100 mg/dL) HDL: 42 mg/dL (reference range: >60 mg/dL) Glucose: 136 mg/dL (reference range: <100 mg/dL) HbA1c: 7.6% (reference range: <5.7%) UFC: 304.5 nmol/24 h (110.3 μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 2.1 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  2. What are your treatment goals for this patient?
  3. What do you consider to be the appropriate next therapy option for this patient?
  4. Would you consider ISTURISA an appropriate option for this patient? Why or why not?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient

Patient portrayal.

Stephanie, Actor Portrayal
BASELINE CHARACTERISTICS Age: 31 Race: African American Height: 5'4” Weight: 75.0 kg (165 lb) BMI: 28.3 kg/m2
Diagnosis High clinical suspicion of hypercortisolemia in Cushing’s syndrome; further testing is required
Time since diagnosis Pending diagnosis
Notes
  • UFC labs were repeated twice over several weeks with consistent findings of elevated cortisol
  • Exogenous sources of hypercortisolemia were ruled out
  • Imaging investigation is required
Treatment
  • None
Status
  • Patient has seen an endocrinologist to discuss lack of symptom relief despite lifestyle modification and reported that symptoms are worsening
Symptoms
  • Weight gain in the abdomen
  • Weight gain in the face
  • Facial plethora
  • Muscle weakness
  • Menstrual irregularities
  • Fatigue and sleep disturbances
  • Anxiety and depression
Comorbidities
  • Diabetes
  • Polycystic ovarian syndrome
Vital signs and labs Blood pressure: 130/84 mm Hg HR: 86 bpm Total cholesterol: 208 mg/dL (reference range: <200 mg/dL) LDL: 106 mg/dL (reference range: <100 mg/dL) HDL: 58 mg/dL (reference range: >60 mg/dL) Glucose: 131 mg/dL (reference range: <100 mg/dL) HbA1c: 7.2% (reference range: <5.7%) UFC: 246.5 nmol/24 h (89.3μg/24 h) (reference range: <145 nmol/24 h [approximately 11-53 μg/24 h]) UFC fold ULN: 1.7 x ULN mUFC

Patient portrayal.

Questions to consider when developing a treatment plan

  1. What symptoms lead you to a high clinical suspicion of hypercortisolemia in Cushing’s syndrome?
  2. What would be the consequences if this patient’s cortisol levels remain uncontrolled?
  3. What are your treatment goals for this patient?

BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

Why ISTURISA May be Right for Your Patient