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.

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.

6.1 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%).

Description of Selected Adverse Reactions

Gastrointestinal Disorders

Gastrointestinal disorders, predominantly nausea, vomiting, diarrhea and abdominal pain were reported in 69% of patients. In many cases, the episodes were of short duration (1-2 days) and the severity was mild to moderate.

Hypocortisolism

Hypocortisolism was reported at a rate of 31% up to 12 weeks, and 18% from Weeks 12 to 26. The majority of cases were manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy.

Changes in Pituitary Tumor Volume

An increase in the pituitary corticotroph tumor volume by greater than 20% from baseline was observed in 21/137 (15%) patients, while a decrease in tumor volume by greater than 20% from baseline was observed in 24/137 (18%) patients at Week 48. Eight patients discontinued because of an increase in tumor volume. There was no correlation between tumor volume increase and increase in adrenocorticotrophic hormone (ACTH). There was no specific pattern of timing of the tumor volume increase and no relationship with the total and the last dose of ISTURISA used in the study.

QTc Interval Prolongation

Adverse reactions of QT prolongation and clinically relevant ECG findings were reported. Five (4%) patients had an event of QT prolongation, 3 (2%) patients had a QTcF increase of > 60 ms from baseline, and 18 (13%) had a new QTcF value of > 450 ms [see Clinical Pharmacology ( 12.2)] .

Accumulation of Adrenal Hormone Precursors

CYP11B1 inhibition by ISTURISA is associated with adrenal steroid precursor accumulation and testosterone increases [see Warnings and Precautions ( 5.3)] . The incidence of adverse reactions potentially related to accumulation of adrenal hormone precursors was 42%. Hypertension and hypokalemia were the most common adrenal hormone precursor-related adverse reactions and occurred in 14% of patients and 17% of patients, respectively; edema was reported in 7% of patients, elevated blood pressure in 15% of patients. All cases of hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone). One patient discontinued the study because of hypokalemia. In male patients testosterone levels generally increased but remained within normal limits; all patients were asymtomatic with no values above upper limit of normal (ULN) at last available value. In female patients, mean testosterone levels increased above the normal range from baseline and reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism (12%) or acne (11%) in a subset of female patients.

Other Abnormal Laboratory Findings

Decreased Absolute Neutrophil Count

Of the 137 patients from the 48-week study, 18 patients had at least one measured absolute neutrophil count below the normal limit, 2 patients had an adverse reaction of neutropenia. No concomitant infections and/or fever were reported in patients with decreased absolute neutrophil count.

Elevated Liver Function Tests

Liver enzyme elevations in patients treated with ISTURISA were infrequent, typically mild and reversed spontaneously or following dose adjustment. Most liver abnormal parameters occurred during the dose-titration period and no patients discontinued ISTURISA drug due to abnormal liver chemistry parameters. Five (4%) patients had ALT or AST > 3 x ULN during the 48-week clinical study.

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

Risk Summary

There are no available data on osilodrostat use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with active Cushing’s Syndrome during pregnancy (see Clinical Considerations).

No adverse developmental outcomes were observed in reproduction studies in pregnant rats and rabbits when exposed to osilodrostat during organogenesis at doses that produced maternal exposures of 7 and 0.5-times the 30 mg twice daily maximum clinical dose, by AUC. In rabbits, exposures associated with maternal toxicity at 7-times the maximum clinical dose resulted in decreased fetal viability. No adverse developmental outcomes were observed in a pre- and postnatal development study with administration of osilodrostat to pregnant rats from organogenesis through lactation at 8-times the 30 mg twice daily maximum clinical dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Active Cushing Syndrome during pregnancy has been associated with an increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, pre-eclampsia, maternal death, miscarriage, fetal loss, and preterm birth).

Data

Animal Data

Osilodrostat administered to pregnant Wistar Han rats from gestation day 6-17 at doses of 0.5, 5, 50 mg/kg did not adversely affect embryo-fetal development up to 5 mg/kg (8-times the 30 mg twice daily maximum clinical dose, by AUC). Maternal toxicity, increased embryonic and fetal deaths, decreased fetal weights, and malformations occurred at 50 mg/kg (118-times the maximum clinical dose, by AUC).

Osilodrostat administered to pregnant New Zealand rabbits from gestation day 7-20 at doses of 3, 10, and 30 mg/kg did not adversely affect embryo-fetal development at 3 mg/kg (0.5-times the 30 mg twice daily maximum clinical dose, by AUC). Maternal toxicity, increased embryo resorption and decreased fetal viability was observed at ≥ 10mg/kg (7-times the maximum clinical dose, by AUC).

Osilodrostat administered to Wistar Han rats from gestation day 6 through lactation day 20 at doses of 1, 5, and 20 mg/kg did not adversely impact behavioral, developmental, or reproductive parameters up to 5 mg/kg (~ 8 times the 30 mg twice daily maximum clinical dose, by AUC). Delayed parturition and dystocia in maternal rats and decreased pup survival were observed at 20 mg/kg (43-times the maximum clinical dose, by AUC).

8.2 Lactation

Risk Summary

There are no available data on the presence of osilodrostat in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions (such as adrenal insufficiency) in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with ISTURISA and for one week after the final dose.

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.

Cardiac Electrophysiology

A thorough QT study in 86 male and female healthy volunteers showed a maximum mean placebo-corrected QTcF interval increase of 1.73 ms [90% confidence interval (CI): 0.15, 3.31] at a 10 mg dose, and 25.38 ms (90% CI: 23.53, 27.22) at a 150 mg dose (up to 2.5 times the maximum recommended dosage) [see Warnings and Precautions ( 5.2)] .

The predicted mean placebo-corrected QTcF change from baseline at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 ms (90% CI: 4.2, 6.5), based on an interpolation of the data from the thorough QT Study and population PK analysis [see Warnings and Precautions ( 5.2)] .

12.3 Pharmacokinetics

Absorption

Osilodrostat is absorbed with a time of maximum observed concentration (T max) of approximately 1 hour. Exposure (AUC inf and C max) slightly increases over dose-proportionally within the therapeutic dose range of 1 mg to 30 mg.

Effect of Food

In a healthy volunteer study (N = 20), subjects administered with a single, 30 mg oral dose of ISTURISA film-coated tablets with a high-fat meal resulted in reduction of AUC by 11% and C max by 21%, respectively. The median T max was delayed from 1 to 2.5 hours. These changes are not considered to be clinically significant, therefore ISTURISA can be administered with or without food.

Distribution

The median apparent volume of distribution of osilodrostat is approximately 100 L. Protein binding is low (36.4%). The osilodrostat blood-to-plasma concentration ratio is 0.85.

Elimination

The elimination half-life of osilodrostat is approximately 4 hours.

In an absorption, distribution, metabolism, and excretion study, the majority of the radioactivity dose of osilodrostat is eliminated in the urine (mean: 90.6% of administered dose) with only a minor amount eliminated in the feces (1.58% of dose). The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.

Metabolism

Multiple CYP enzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes greater than 25% to the total clearance. The metabolites are not expected to contribute to the pharmacological effect of osilodrostat.

Specific Populations

Age and gender have no significant impact on osilodrostat exposure in adults.

Race/Ethnicity

The relative bioavailability in Asian patients is approximately 20% higher compared to that of non-Asian, along with higher T max and C max, compared to other ethnicities. However, the difference is not clinically significant.

Patients with Renal Impairment

Osilodrostat exposure was similar in the three renal function groups [normal, severe, and end stage renal disease (ESRD) groups] and thus a study was not conducted in mild and moderate renal impairment groups. The results showed that the PK of osilodrostat was not influenced by varying degrees of renal impairment to any clinically significant extent [see Dosage and Administration ( 2.4), Use in Specific Populations ( 8.6)] .

Patients with Hepatic Impairment

There was a trend of increasing AUC inf to osilodrostat in moderate and severe hepatic impaired subjects (geo-mean ratios are 1.44 and 2.66, respectively) as compared to normal subjects. Exposures (C max and AUC) of osilodrostat in the mild hepatic impairment group were similar to those in the normal group [see Dosage and Administration ( 2.5), Use in Specific Populations ( 8.7)] .

Drug Interaction

In a healthy volunteer study (N = 20) using a single dose of osilodrostat (50 mg) and a probe drugs cocktail, osilodrostat showed inhibition potential on CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 isozymes with 2.5-, 1.9-, 1.5- and 1.5-fold increase in caffeine, omeprazole, dextromethorphan, and midazolam exposure, respectively [see Drug Interactions ( 7.1), ( 7.2)] .

There was no significant impact of osilodrostat (30 mg twice daily for 12 days) on the exposure of oral contraceptives containing 0.03 mg estradiol and 0.15 mg levonorgestrel in healthy female subjects.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in Wistar Han rats and CD1 mice. Hepatocellular adenomas and carcinomas occurred in male rats at ≥ 10 mg/kg and in females at 30 mg/kg (18- and 65-times the 30 mg twice daily maximum clinical dose, by AUC, respectively). Thyroid follicular adenoma/carcinoma was also observed in male rats at 30 mg/kg. Hepatocellular adenomas and carcinomas occurred in male mice at ≥ 10 mg kg (6 times the maximum clinical dose, by AUC) but not in female mice at any dose ≤ 30 mg/kg (31 times the maximum clinical dose, by AUC). These findings are likely rodent specific and considered not relevant to humans. Genetic profiling studies support activation of hepatic constitutive androstane receptors as the likely tumorigenic mechanism in rodents and is not a significant concern for human risk at clinical exposure to osilodrostat.

Genotoxicity

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation indicate that there is no genotoxic risk in humans with osilodrostat.

Impairment of Fertility

In a fertility and early embryonic-development study in Wistar Han rats, doses of 50 mg/kg (118 times the 30 mg twice daily maximum clinical dose, by AUC) resulted in changes to estrous cyclicity and impaired female fertility and embryo viability. No effect on reproductive performance in females was observed at 5 mg/kg (8 times the maximum clinical dose). Fertility and reproductive performance were not affected in male rats up to 50 mg/kg (77 times the maximum clinical dose, by AUC).