Isturisa

Osilodrostat · Tablet, Coated · Oral

Prescription (Rx) Cortisol Synthesis Inhibitor

Uses

1 INDICATIONS AND USAGE 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. ISTURISA is a cortisol synthesis inhibitor 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 ( 1 )

Dosage and administration

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 ) 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 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. 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.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS 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. Tablets: 1 mg and 5 mg ( 3 )

Contraindications

None. None ( 4 )

Warnings and precautions

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 ) 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. 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. 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.

Side effects

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) ] Most common adverse reactions (incidence > 20%) are adrenal insufficiency, fatigue, nausea, headache, edema, decreased appetite, arthralgia, myalgia, and diarrhea ( 6 ) 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. 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. 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) ] . Study 1 The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1. Table 1: Adverse Reactions With a Frequency of More Than 10% in 48-week Clinical Study 1 in Adults with Cushing's Disease Adverse Reaction Type (N = 137) % Adrenal insufficiency Adrenal 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. 43.1 Fatigue Fatigue includes lethargy, asthenia. 38.7 Nausea 37.2 Headache Headache includes head discomfort. 30.7 Edema Edema includes edema peripheral, generalized edema, localized edema. 21.2 Nasopharyngitis 19.7 Vomiting 19 Arthralgia 17.5 Back pain 15.3 Rash Rash includes rash erythematous, rash generalized, rash maculopapular, rash papular. 15.3 Diarrhea 14.6 Blood corticotrophin increased 13.9 Dizziness Dizziness includes dizziness postural. 13.9 Abdominal pain Abdominal pain includes abdominal pain upper, abdominal discomfort 13.1 Hypokalemia Hypokalemia includes blood potassium decreased. 12.4 Myalgia 12.4 Decreased appetite 11.7 Hormone level abnormal 11.7 Hypotension Hypotension includes orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. 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 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 Select Adverse Reactions from the Core 48-week Period of Study 1 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 > 60ms from baseline, and 18 (13%) had a new QTcF value of > 450ms [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 asymptomatic with no values above upper limit of normal (ULN) at last available value.

Drug interactions

7 DRUG INTERACTIONS 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 ) 7.1 Effect of Other Drugs on ISTURISA The effect of other drugs on ISTURISA can be found in Table 3. Table 3: Effect of Other Drugs on ISTURISA CYP3A4 Inhibitors Clinical Impact: Concomitant use of ISTURISA with a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin) may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention : Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor. CYP3A4 and CYP2B6 Inducers Clinical Impact: Concomitant use of ISTURISA with strong CYP3A4 and/or CYP2B6 inducers (e.g., carbamazepine, rifampin, phenobarbital) may cause a decrease in osilodrostat concentration and may reduce the efficacy of ISTURISA [see Clinical Pharmacology (12.3) ] . Discontinuation of strong CYP3A4 and/or CYP2B6 inducers while using ISTURISA may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention: During concomitant use of ISTURISA with strong CYP3A4 and CYP2B6 inducers, monitor cortisol concentration and patient's signs and symptoms. An increase in ISTURISA dosage may be needed. Upon discontinuation of strong CYP3A4 and CYP2B6 inducers during ISTURISA treatment, monitor cortisol concentration and patient's signs and symptoms. A reduction in ISTURISA dosage may be needed. 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) ] .

Use in specific populations

Lactation : Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment ( 8.2 ) 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 30mg 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 3mg/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.

Pregnancy

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 30mg 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 3mg/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).

Pediatric use

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

Geriatric use

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) ] .

Overdosage

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.

Description

(osilodrostat) is a cortisol synthesis inhibitor. The chemical name of osilodrostat is 4-[(5 R )-6,7-Dihydro-5 H -pyrrolo[1,2- c ]imidazol-5-yl]-3-fluorobenzonitrile dihydrogen phosphate. Molecular formula of osilodrostat salt (phosphate) form on anhydrous basis is: (C 13 H 11 FN 3 ) (H 2 PO 4 ). 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. Chemical Structure

Mechanism of action

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).

How supplied

How Supplied ISTURISA (osilodrostat) tablets are supplied as follows: Tablet Strength Description Package Configuration NDC No. 1 mg Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed "1" on one side. Each carton contains 6 blister packs for a total of 60 tablets. Each blister pack contains 10 tablets. 55292-330-60 5 mg Yellow, unscored, round, biconvex with beveled edge tablet, debossed "5" on one side. 55292-331-60 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.

Storage

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.

Patient information

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

Label text from the FDA structured product label by Recordati Rare Diseases, Inc. (revised Nov 18, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Osilodrostat Phosphate in 4 products

Isturisa NDC products (4)

NDC	Strength & form	Labeler	Type
55292-320	Osilodrostat Phosphate 1 mg/1 Tablet, Coated	Recordati Rare Diseases, Inc.	NDA
55292-321	Osilodrostat Phosphate 5 mg/1 Tablet, Coated	Recordati Rare Diseases, Inc.	NDA
55292-330	Osilodrostat Phosphate 1 mg/1 Tablet, Coated	Recordati Rare Diseases, Inc.	NDA
55292-331	Osilodrostat Phosphate 5 mg/1 Tablet, Coated	Recordati Rare Diseases, Inc.	NDA

Frequently asked questions

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Isturisa is listed by 1 labeler in the FDA NDC directory, including Recordati Rare Diseases, Inc..