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 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 1-2 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.

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, bradyarrhythmias, 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.

6.1 Clinical Trials Experience

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.

A total of 137 Cushing's disease patients were exposed to ISTURISA in the study [see Clinical Studies (14)]. 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%).

7.1 Effect of Other Drugs on ISTURISA

The effect of other drugs on ISTURISA can be found in Table 2.

7.2 Effect of ISTURISA on Other Drugs

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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

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)].

8.6 Renal Impairment

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.

8.7 Hepatic Impairment

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.

12.1 Mechanism of Action

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).

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Period 1 (Week 1 to 12)

137 patients received a starting dose of 2 mg ISTURISA orally twice daily that could be titrated up to a maximum of 30 mg twice daily at no greater than 2-week intervals to achieve a mUFC within the normal range. Individual dose adjustments were based on mUFC. The dose was increased if mUFC was above ULN and was reduced if mUFC was below the lower limit of normal (LLN), or if the patient had symptoms consistent with hypocortisolism and mUFC was in the lower part of the normal range.

Period 2 (Week 13 to 24)

130 patients entered Period 2. The daily dose for patients that achieved a mUFC within the normal range in Period 1 was maintained during Period 2. Patients who did not require further dose increase, tolerated the drug, and had a mUFC ≤ ULN at Week 24 (end of Period 2) were to be considered responders and eligible to enter the Randomization Withdrawal phase (Period 3). Patients whose mUFC became elevated during Period 2 could have their dose increased further, if tolerated, up to 30 mg twice daily. These patients were considered non-responders and did not enter Period 3 but continued open-label treatment together with the patients who did not achieve normal mUFC at Week 12 and were followed for long-term safety and response to treatment.

Period 3 (Week 26 to 34)

At Week 26, 71 patients were considered responders and were randomized 1:1 to continue receiving ISTURISA (n = 36) or to switch to placebo (n = 35) for 8 weeks. Patients were stratified at randomization according to dose received at Week 24 (≤ 5 mg twice daily vs 5 mg twice daily) and history of pituitary irradiation (yes/no).

Patients were to remain on their assigned treatment and dose throughout Period 3 if mUFC were within the normal range. Blinded dose reduction or temporary discontinuation for safety or tolerability reasons were permitted. Dose increases were not permitted during Period 3. Patients with mUFC increase > 1.5 × ULN or who required a dose increase were considered non-responders and discontinued from Period 3 but allowed to receive open-label treatment during Period 4.

Period 4 (Week 26 or 34 to 48)

This period included patients who were not eligible for randomization (n = 47) at Week 26, patients who were considered non-responders during Period 3 (n = 29), and patients who were considered responders during Period 3 (n = 41). Open-label treatment with ISTURISA continued in these patients until Week 48 when patients who maintained clinical benefit on ISTURISA, as judged by the Investigator, had an option to enter an extension period.

Efficacy Assessment

The primary efficacy endpoint of the study was to compare the percentage of complete responders at the end of the 8-week randomized withdrawal period (Period 3) between patients randomized to continue ISTURISA versus the patients switched to placebo. A complete responder for the primary endpoint was defined as a patient who had mUFC ≤ ULN based on central laboratory result at the end of Period 3 (Week 34), and who neither discontinued randomized treatment or the study nor had any dose increase above their Week 26 dose.

The key secondary endpoint was to assess the complete responder rate at the end of Period 2 (Week 24). A complete responder for the key secondary endpoint was defined as a patient with mUFC ≤ ULN at Week 24 who did not require an increase in dose above the level established at the end of Period 1 (Week 12). Patients who were missing mUFC assessment at Week 24 were counted as non-responders for the key secondary endpoint.

How Supplied

ISTURISA (osilodrostat) tablets are supplied as follows:

Storage and Handling

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

Monitoring

Instruct patients on the importance of laboratory monitoring and adhering to their return visit schedule [see Dosage and Administration (2.2, 2.3)].

Hypocortisolism

Advise patients that ISTURISA is associated with hypocortisolism-related events. Advise patients to report symptoms of hypercortisolism to their healthcare provider [see Warnings and Precautions (5.1)].

QT Prolongation

Advise patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation.

Advise patients that an ECG will be taken before treatment and periodically thereafter. Advise patients with cardiac disease and risk factors for QT prolongation that adjustments in cardiac medications may be made and electrolyte disturbances may require correction [see Warnings and Precautions (5.2)].

Adrenal Hormone Precursors/Androgens

Advise patients that elevation of adrenal hormone precursors may occur and lead to low potassium levels, worsening of hypertension, and edema. Advise patients to report the occurrence of these symptoms to their healthcare provider.

Advise patients that elevations of androgens may occur and may lead to hirsutism, hypertrichosis, and acne (in females). Advise patients to report the occurrence of these symptoms to their healthcare provider [see Warnings and Precautions (5.3)].

Lactation

Advise females not to breastfeed during treatment with ISTURISA and for at least one week after treatment [see Use in Specific Populations (8.2)].