Safety

An Expected and Manageable Safety Profile Demonstrated Through 48 Weeks1

Adverse reactions among patients with Cushing’s disease who received at least one dose of ISTURISA in the study:

Adverse reactions that occurred in more than 10% of patients (N=137)

Adverse reaction %
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
Diarrhea 14.6
Blood corticotrophin increased 13.9
Dizzinessf 13.9
Adverse reaction %
Abdominal paing 13.1
Hypokalemiah 12.4
Myalgia 12.4
Decreased appetite 11.7
Hormone level abnormal 11.7
Hypotensioni 11.7
Urinary tract infection 11.7
Blood testosterone increased 10.9
Pyrexia 10.9
Anemia 10.2
Cough 10.2
Hypertension 10.2
Influenza 10.2

These are not all the possible side effects of ISTURISA. Please refer to section 6 (Adverse Reactions) in the full Prescribing Information.

  • aAdrenal 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.
  • bFatigue includes lethargy, asthenia.
  • cHeadache includes head discomfort.
  • dEdema includes edema peripheral, generalized edema, localized edema.
  • eRash includes rash erythematous, rash generalized, rash maculopapular, rash papular.
  • fDizziness includes dizziness postural.
  • gAbdominal pain includes abdominal pain upper, abdominal discomfort.
  • hHypokalemia includes blood potassium decreased.
  • iHypotension includes orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased.
  • Hypocortisolism was reported at a rate of 31% during weeks 1 to 12 and 18% during weeks 12 to 26
    • Hypocortisolism is manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy

43.1% of patients had adrenal insufficiency1

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

of the subjects with this event had low cortisol levels indicative of adrenal insufficiency

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.

Reference: 1. ISTURISA® (osilodrostat) [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020.