Isturisa

ISTURISA- osilodrostat phosphate tablet, coated
Recordati Rare Diseases, Inc.

1 INDICATIONS AND USAGE

ISTURISA 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.

2 DOSAGE AND ADMINISTRATION

2.1 Laboratory Testing Prior to ISTURISA Initiation

  • Correct hypokalemia and hypomagnesemia prior to starting ISTURISA [see Warnings and Precautions ( 5.2, 5.3)] .
  • Obtain baseline electrocardiogram (ECG). Repeat ECG within one week after treatment initiation, and as clinically indicated thereafter [see Warnings and Precautions ( 5.2)] .

2.2 Recommended Dosage, Titration, and Monitoring

  • Initiate dosing at 2 mg orally twice daily, with or without food.
  • Initially, titrate the dosage 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 urine free cortisol (UFC) levels above upper normal limit, the dosage can be titrated further by 5 mg twice daily every 2 weeks. Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 1-2 weeks until adequate clinical response is maintained.
  • The maintenance dosage of ISTURISA is individualized and determined by titration based on cortisol levels and patient’s signs and symptoms.
  • The maintenance dosage varied between 2 mg and 7 mg twice daily in clinical trials. The maximum recommended maintenance dosage of ISTURISA is 30 mg twice daily.
  • Once the maintenance dosage is achieved, monitor cortisol levels at least every 1-2 months or as indicated.

2.3 Dosage Interruptions and Modifications

  • 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. If necessary, glucocorticoid replacement therapy should be initiated.
  • 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 [see Warnings and Precautions ( 5.1)] .
  • If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.

2.4 Recommended Dosage and Monitoring in Patients with Renal Impairment

  • No dose adjustment is required for patients with renal impairment. Use caution in interpreting urine free cortisol levels in patients with moderate to severe renal impairment, due to reduced urine free cortisol excretion [see Clinical Pharmacology ( 12.3)] .

2.5 Recommended Dosage and Monitoring in Patients with Hepatic Impairment

  • For patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose 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.
  • No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A).
  • More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment [see Clinical Pharmacology ( 12.3)] .

2.6 Missed Dose

If a dose of ISTURISA is missed, the patient should take their next dose at the regularly scheduled time.

3 DOSAGE FORMS AND STRENGTHS

ISTURISA is available as:

  • 1 mg tablets: Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed “Y1” on one side and “NVR” on the other side.
  • 5 mg tablets: Yellow, unscored, round, biconvex with beveled edge tablet, debossed “Y2” on one side and “NVR” on the other side.
  • 10 mg tablets: Pale orange brown, unscored, round, biconvex with beveled edge tablet, debossed “Y3” on one side and “NVR” on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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, dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia [see Adverse Reactions ( 6)] .

Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour 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. Re-initiate ISTURISA at a lower dose when urine free cortisol, serum or plasma cortisol levels are within target range, and/or patient symptoms have resolved. 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.

5.2 QTc Prolongation

ISTURISA is associated with a dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias [see Adverse Reactions ( 6), Clinical Pharmacology ( 12.2)] .

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. Correct electrolyte abnormalities if indicated. Consider temporary discontinuation of ISTURISA in the case of an increase in QTc interval > 480 ms.

Use caution in patients with risk factors for QT prolongation, (such as congenital long QT syndrome, congestive heart failure, bradyarrythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring.

5.3 Elevations in Adrenal Hormone Precursors and Androgens

ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens.

Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension [see Adverse Reactions ( 6)] . Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. ISTURISA-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists. ISTURISA dose reduction or discontinuation may be necessary.

Accumulation of androgens may lead to hirsutism, hypertrichosis and acne (in females). Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.

6 ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other sections of the labeling include:

  • Hypocortisolism [see Warnings and Precautions ( 5.1)]
  • QT Prolongation [see Warnings and Precautions ( 5.2)]
  • Elevations in Adrenal Hormone Precursors and Androgens [see Warnings and Precautions ( 5.3)]

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