These Highlights Do Not Include All The Information Needed To Use Isturisa®

Study 1

The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1.

Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%).

Storage and Handling

Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F); protect from moisture.

The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study (called the Core Period) that consisted of four study periods as follows:

• Period 1: 12-week, open-label, dose titration period
• Period 2: 12-week, open-label, maintenance treatment period
• Period 3: 8-week, double-blind, placebo-controlled, randomized withdrawal treatment period which provided the data for the primary efficacy endpoint
• Period 4: open-label treatment period of 14 to 24 weeks duration

The mean age at enrollment was 41 years; 77% of patients were female. There were 65% Caucasian, 28% Asian, 3% black, and 4% other race. Overall, 96% 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 UFC (mUFC) > 1.5× upper limit of normal (ULN). The mean mUFC (SD) at baseline was 1006 nmol/24 hr (1589) (365 mcg/24 hr), which corresponds to approximately 7 × ULN. The median mUFC at baseline was 476 nmol/24 hr (173 mcg/24 hr), which corresponds to approximately 3.5 × ULN.

The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study that consisted of two core study periods as follows:

• Period 1: 12-week, double-blind, placebo-controlled, randomized treatment period with ISTURISA or placebo.
• Period 2: 36-week, open-label, treatment period with ISTURISA.

Study 2 enrolled 74 patients with Cushing's disease, of whom 73 were treated. The mean (range) age at enrollment was 41 (19 to 67) years; 84% were female. There was 67% Caucasian, 23% Asian, 3% black, and 7% other race. Overall, 96% of patients had persistent/recurring Cushing's disease prior to entering the study, of which 88% had undergone previous surgery and 62% of patients had prior medical treatment for Cushing's disease. Persistence or recurrence of Cushing's disease was evidenced by the mean of three 24-hour UFC (mUFC) > 1.3× upper limit of normal (ULN). The mean mUFC (SD) at baseline was 432 nmol/24hr (389) (157 mcg/24 hr), which corresponds to approximately 3.1 × ULN. The median mUFC at baseline was 340 nmol/24hr (123 mcg/24 hr), which corresponds to approximately 2.5 × ULN.

Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness, and syncope.

In case of suspected overdosage, ISTURISA should be temporarily discontinued, cortisol levels should be checked, and if necessary, corticosteroid supplementation should be initiated. Close surveillance may be necessary, including monitoring of the QT interval, blood pressure, glucose, fluid, and electrolyte until the patient's condition is stable.

ISTURISA (osilodrostat) is a cortisol synthesis inhibitor.

The chemical name of osilodrostat is 4-[(5R)-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile dihydrogen phosphate.

Molecular formula of osilodrostat salt (phosphate) form on anhydrous basis is: (C₁₃H₁₁FN₃) (H₂PO₄). Relative molecular mass of osilodrostat phosphate salt form is 325.24 g/mol.

ISTURISA tablets for oral administration contains 1 mg or 5 mg of osilodrostat equivalent to 1.4 mg or 7.2 mg of osilodrostat phosphate respectively, and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, and magnesium stearate. The film coat is composed of hypromellose, titanium dioxide, ferric oxide (yellow), ferric oxide (red) (1 mg only), polyethylene glycol 4000, and talc.

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

The safety and effectiveness of ISTURISA in pediatric patients have not been established.

Of the 167 patients in clinical trials with ISTURISA, 10 (6%) were 65 years and older. There were no patients above 75 years of age. Based on the available data on the use of ISTURISA in patients older than 65 years, no dosage adjustment is required [see Clinical Pharmacology (12.3)].

The safety and efficacy of ISTURISA was evaluated in 2 multicenter clinical studies, Study 1 (NCT02180217) and Study 2 (NCT02697734), in adults with persistent or recurrent Cushing's disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. Study 1 was a 48-week study that included an 8-week, double-blind, randomized withdrawal period at Weeks 26 to 34 in the study. After Week 48, patients who maintained clinical benefit on ISTURISA could continue in a long-term extension period until the last patient reached Week 72. Study 2 was a 48-week study in which patients were randomized 2:1 to ISTURISA or placebo and treated for 12 weeks followed by a 36-week open-label treatment. After completion of week 48, patients who maintained clinical benefit on ISTURISA could continue on ISTURISA in an optional 48-week extension period.

None.

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. After interruption or discontinuation of ISTURISA, cortisol suppression may persist beyond the 4 hour half-life. Monitor patients regularly and 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.

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

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)]

• CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor (7.1)
• 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 (7.1)

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, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring.

No dosage adjustment of ISTURISA in patients with impaired renal function is required [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. In patients with moderate to severe renal impairment, UFC levels should be interpreted with caution due to reduced UFC excretion.

A dose dependent increase was observed in 11-deoxycortisol, the cortisol precursor, and ACTH levels in patients with Cushing's disease.

Dosage adjustment is not required in patients with mild hepatic impairment (Child-Pugh A) but is required for patients with moderately impaired hepatic function (Child-Pugh B) and for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment.

ISTURISA 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.

Osilodrostat is a cortisol synthesis inhibitor. It inhibits 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. In a Chinese hamster lung cell line V79-4 that overexpresses human CYP11B1, adrenodoxin and adrenodoxin reductase, osilodrostat inhibited the activity of human CYP11B1 dose-dependently with IC50 values of 2.5 ± 0.1 nM (n = 4).

• Hypocortisolism: Monitor patients closely for hypocortisolism and potentially life-threatening adrenal insufficiency. Dosage reduction or interruption may be necessary. After interruption or discontinuation of ISTURISA, cortisol suppression may persist and patients should be regularly monitored (5.1)
• QTc Prolongation: Perform electrocardiogram in all patients Use with caution in patients with risk factors for QTc prolongation (5.2)
• Elevations in Adrenal Hormone Precursors and Androgens: Monitor for hypokalemia, worsening of hypertension, edema, and hirsutism (5.3)

• Correct hypokalemia and hypomagnesemia, and obtain baseline electrocardiogram prior to starting ISTURISA (2.1, 5.2, 5.3)
• Initiate dosage at 2 mg orally twice daily, with or without food (2.2)
• Titrate dosage by 1 mg to 2 mg twice daily, no more frequently than every 2 weeks based on rate of cortisol changes, individual tolerability and improvement in signs and symptoms (2.2)
• Maximum recommended dosage is 30 mg twice daily (2.2)
• See Full Prescribing Information for complete titration, laboratory, and dosage modification recommendations (2.1, 2.2, 2.3)
• Patients with Hepatic Impairment:
  • Child-Pugh B: Recommended starting dose is 1 mg twice daily (2.5, 8.7 )
  • Child-Pugh C: Recommended starting dose is 1 mg once daily in the evening (2.5, 8.7)

ISTURISA is available as:

• 1 mg tablets: Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed "1" on one side.
• 5 mg tablets: Yellow, unscored, round, biconvex with beveled edge tablet, debossed "5" on one side.

Additional adverse reactions have been identified during postapproval use of ISTURISA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Neutropenia associated with fever and infection

• Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ISTURISA was evaluated in two clinical trials in adults with Cushings disease. Study 1 (NCT02180217) was a 4-period, multicenter study with a 12-week open-label titration period, 12-week open-label maintenance period, 8-week double-blind, placebo-controlled period, and 14 to 24-week open label treatment period in 137 patients with Cushing's disease. Study 2 (NCT02697734) was a 2-period, multicenter study with a 12-week randomized, double-blind, placebo-controlled period and a 36-week open-label treatment period in 74 patients with Cushing's disease [see Clinical Studies (14)].

Advise patients to read the FDA-approved patient labeling (Patient Information).

The effect of other drugs on ISTURISA can be found in Table 3.

ISTURISA should be used with caution when coadministered with CYP1A2 and CYP2C19 substrates with a narrow therapeutic index, such as theophylline, tizanidine, and S-mephenytoin [see Clinical Pharmacology (12.3)].

• 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.

• Initiate dosing at 2 mg orally twice daily, with or without food.
• Initially, titrate the dosage by 1 mg 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 syndrome. 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 to 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 [see Clinical Studies (14)].
• Once the maintenance dosage is achieved, monitor cortisol levels at least every 1 to 2 months or as indicated.

NDC 55292-330-60

Isturisa^® 1 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 1 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

NDC 55292-331-60

Isturisa^® 5 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 5 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

• 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)].

NDC 55292-322-60

Isturisa^® 10 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 10 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

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.

• 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)].

• 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)].

Study 1

The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1.

Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%).

Storage and Handling

Store at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F); protect from moisture.

The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study (called the Core Period) that consisted of four study periods as follows:

• Period 1: 12-week, open-label, dose titration period
• Period 2: 12-week, open-label, maintenance treatment period
• Period 3: 8-week, double-blind, placebo-controlled, randomized withdrawal treatment period which provided the data for the primary efficacy endpoint
• Period 4: open-label treatment period of 14 to 24 weeks duration

The mean age at enrollment was 41 years; 77% of patients were female. There were 65% Caucasian, 28% Asian, 3% black, and 4% other race. Overall, 96% 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 UFC (mUFC) > 1.5× upper limit of normal (ULN). The mean mUFC (SD) at baseline was 1006 nmol/24 hr (1589) (365 mcg/24 hr), which corresponds to approximately 7 × ULN. The median mUFC at baseline was 476 nmol/24 hr (173 mcg/24 hr), which corresponds to approximately 3.5 × ULN.

The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study that consisted of two core study periods as follows:

• Period 1: 12-week, double-blind, placebo-controlled, randomized treatment period with ISTURISA or placebo.
• Period 2: 36-week, open-label, treatment period with ISTURISA.

Study 2 enrolled 74 patients with Cushing's disease, of whom 73 were treated. The mean (range) age at enrollment was 41 (19 to 67) years; 84% were female. There was 67% Caucasian, 23% Asian, 3% black, and 7% other race. Overall, 96% of patients had persistent/recurring Cushing's disease prior to entering the study, of which 88% had undergone previous surgery and 62% of patients had prior medical treatment for Cushing's disease. Persistence or recurrence of Cushing's disease was evidenced by the mean of three 24-hour UFC (mUFC) > 1.3× upper limit of normal (ULN). The mean mUFC (SD) at baseline was 432 nmol/24hr (389) (157 mcg/24 hr), which corresponds to approximately 3.1 × ULN. The median mUFC at baseline was 340 nmol/24hr (123 mcg/24 hr), which corresponds to approximately 2.5 × ULN.

Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness, and syncope.

In case of suspected overdosage, ISTURISA should be temporarily discontinued, cortisol levels should be checked, and if necessary, corticosteroid supplementation should be initiated. Close surveillance may be necessary, including monitoring of the QT interval, blood pressure, glucose, fluid, and electrolyte until the patient's condition is stable.

ISTURISA (osilodrostat) is a cortisol synthesis inhibitor.

The chemical name of osilodrostat is 4-[(5R)-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile dihydrogen phosphate.

Molecular formula of osilodrostat salt (phosphate) form on anhydrous basis is: (C₁₃H₁₁FN₃) (H₂PO₄). Relative molecular mass of osilodrostat phosphate salt form is 325.24 g/mol.

ISTURISA tablets for oral administration contains 1 mg or 5 mg of osilodrostat equivalent to 1.4 mg or 7.2 mg of osilodrostat phosphate respectively, and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, and magnesium stearate. The film coat is composed of hypromellose, titanium dioxide, ferric oxide (yellow), ferric oxide (red) (1 mg only), polyethylene glycol 4000, and talc.

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

The safety and effectiveness of ISTURISA in pediatric patients have not been established.

Of the 167 patients in clinical trials with ISTURISA, 10 (6%) were 65 years and older. There were no patients above 75 years of age. Based on the available data on the use of ISTURISA in patients older than 65 years, no dosage adjustment is required [see Clinical Pharmacology (12.3)].

The safety and efficacy of ISTURISA was evaluated in 2 multicenter clinical studies, Study 1 (NCT02180217) and Study 2 (NCT02697734), in adults with persistent or recurrent Cushing's disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. Study 1 was a 48-week study that included an 8-week, double-blind, randomized withdrawal period at Weeks 26 to 34 in the study. After Week 48, patients who maintained clinical benefit on ISTURISA could continue in a long-term extension period until the last patient reached Week 72. Study 2 was a 48-week study in which patients were randomized 2:1 to ISTURISA or placebo and treated for 12 weeks followed by a 36-week open-label treatment. After completion of week 48, patients who maintained clinical benefit on ISTURISA could continue on ISTURISA in an optional 48-week extension period.

None.

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. After interruption or discontinuation of ISTURISA, cortisol suppression may persist beyond the 4 hour half-life. Monitor patients regularly and 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.

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

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)]

• CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor (7.1)
• 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 (7.1)

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, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring.

No dosage adjustment of ISTURISA in patients with impaired renal function is required [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. In patients with moderate to severe renal impairment, UFC levels should be interpreted with caution due to reduced UFC excretion.

A dose dependent increase was observed in 11-deoxycortisol, the cortisol precursor, and ACTH levels in patients with Cushing's disease.

Dosage adjustment is not required in patients with mild hepatic impairment (Child-Pugh A) but is required for patients with moderately impaired hepatic function (Child-Pugh B) and for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment.

ISTURISA 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.

Osilodrostat is a cortisol synthesis inhibitor. It inhibits 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. In a Chinese hamster lung cell line V79-4 that overexpresses human CYP11B1, adrenodoxin and adrenodoxin reductase, osilodrostat inhibited the activity of human CYP11B1 dose-dependently with IC50 values of 2.5 ± 0.1 nM (n = 4).

• Hypocortisolism: Monitor patients closely for hypocortisolism and potentially life-threatening adrenal insufficiency. Dosage reduction or interruption may be necessary. After interruption or discontinuation of ISTURISA, cortisol suppression may persist and patients should be regularly monitored (5.1)
• QTc Prolongation: Perform electrocardiogram in all patients Use with caution in patients with risk factors for QTc prolongation (5.2)
• Elevations in Adrenal Hormone Precursors and Androgens: Monitor for hypokalemia, worsening of hypertension, edema, and hirsutism (5.3)

• Correct hypokalemia and hypomagnesemia, and obtain baseline electrocardiogram prior to starting ISTURISA (2.1, 5.2, 5.3)
• Initiate dosage at 2 mg orally twice daily, with or without food (2.2)
• Titrate dosage by 1 mg to 2 mg twice daily, no more frequently than every 2 weeks based on rate of cortisol changes, individual tolerability and improvement in signs and symptoms (2.2)
• Maximum recommended dosage is 30 mg twice daily (2.2)
• See Full Prescribing Information for complete titration, laboratory, and dosage modification recommendations (2.1, 2.2, 2.3)
• Patients with Hepatic Impairment:
  • Child-Pugh B: Recommended starting dose is 1 mg twice daily (2.5, 8.7 )
  • Child-Pugh C: Recommended starting dose is 1 mg once daily in the evening (2.5, 8.7)

ISTURISA is available as:

• 1 mg tablets: Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed "1" on one side.
• 5 mg tablets: Yellow, unscored, round, biconvex with beveled edge tablet, debossed "5" on one side.

Additional adverse reactions have been identified during postapproval use of ISTURISA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Neutropenia associated with fever and infection

• Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ISTURISA was evaluated in two clinical trials in adults with Cushings disease. Study 1 (NCT02180217) was a 4-period, multicenter study with a 12-week open-label titration period, 12-week open-label maintenance period, 8-week double-blind, placebo-controlled period, and 14 to 24-week open label treatment period in 137 patients with Cushing's disease. Study 2 (NCT02697734) was a 2-period, multicenter study with a 12-week randomized, double-blind, placebo-controlled period and a 36-week open-label treatment period in 74 patients with Cushing's disease [see Clinical Studies (14)].

Advise patients to read the FDA-approved patient labeling (Patient Information).

The effect of other drugs on ISTURISA can be found in Table 3.

ISTURISA should be used with caution when coadministered with CYP1A2 and CYP2C19 substrates with a narrow therapeutic index, such as theophylline, tizanidine, and S-mephenytoin [see Clinical Pharmacology (12.3)].

• 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.

• Initiate dosing at 2 mg orally twice daily, with or without food.
• Initially, titrate the dosage by 1 mg 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 syndrome. 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 to 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 [see Clinical Studies (14)].
• Once the maintenance dosage is achieved, monitor cortisol levels at least every 1 to 2 months or as indicated.

NDC 55292-330-60

Isturisa^® 1 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 1 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

NDC 55292-331-60

Isturisa^® 5 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 5 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

• 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)].

NDC 55292-322-60

Isturisa^® 10 mg

(osilodrostat)

tablets

Rx only

Each tablet contains 10 mg osilodrostat (as osilodrostat phosphate).

60 film-coated tablets

RECORDATI

RARE DISEASES

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.

• 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)].

• 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)].