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Osilodrostat

Class: Other Miscellaneous Therapeutic Agents
Chemical Name: 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile
Molecular Formula: C13H10FN3
CAS Number: 1304733-26-3
Brands: Isturisa

Introduction

Osilodrostat phosphate is a cortisol synthesis inhibitor.1

Uses for Osilodrostat

Osilodrostat phosphate has the following uses:

Osilodrostat phosphate is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.1

Osilodrostat Dosage and Administration

General

Osilodrostat phosphate is available in the following dosage form(s) and strength(s):

Tablets: 1 mg, 5 mg, and 10 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Correct hypokalemia and hypomagnesemia, and obtain baseline electrocardiogram prior to starting osilodrostat phosphate.1

  • Initiate dosage at 2 mg orally twice daily, with or without food.1

  • Titrate dosage by 1 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.1

  • Maximum recommended dosage is 30 mg twice daily.1

  • See Full Prescribing Information for complete titration, laboratory, and dosage modification recommendations.1

  • Moderate hepatic impairment (Child-Pugh B): Recommended starting dose is 1 mg twice daily.1

  • Severe hepatic impairment (Child-Pugh C): Recommended starting dose is 1 mg once daily in the evening.1

Cautions for Osilodrostat

Contraindications

None.1

Warnings/Precautions

Hypocortisolism

Osilodrostat phosphate 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.1

Hypocortisolism can occur at any time during osilodrostat phosphate treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour urine free cortisol (UFC), serum or plasma cortisol, and patient’s signs and symptoms periodically during osilodrostat phosphate treatment.1

Decrease or temporarily discontinue osilodrostat phosphate 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 osilodrostat phosphate 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 osilodrostat phosphate at a lower dose when urine free cortisol, serum or plasma cortisol levels are within target range, and/or patient symptoms have resolved. After osilodrostat phosphate discontinuation, cortisol suppression may persist beyond the 4 hour half-life of osilodrostat phosphate.1

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.1

QTc Prolongation

Osilodrostat phosphate 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.1

Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with osilodrostat phosphate and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to osilodrostat phosphate initiation and monitor periodically during treatment with osilodrostat phosphate. Correct electrolyte abnormalities if indicated. Consider temporary discontinuation of osilodrostat phosphate in the case of an increase in QTc interval > 480 ms.1

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.1

Elevations in Adrenal Hormone Precursors and Androgens

Osilodrostat phosphate blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens.1

Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating osilodrostat phosphate. Monitor patients treated with osilodrostat phosphate for hypokalemia, worsening of hypertension and edema. Osilodrostat phosphate-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. Osilodrostat phosphate dose reduction or discontinuation may be necessary.1

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.1

Specific Populations

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.1

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.1

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.1

Clinical Considerations: 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).1

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).1

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).1

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).1

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 osilodrostat phosphate and for one week after the final dose.1

Pediatric Use

The safety and effectiveness of osilodrostat phosphate in pediatric patients have not been established.1

Geriatric Use

Of the 167 patients in clinical trials with osilodrostat phosphate, 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 osilodrostat phosphate in patients older than 65 years, no dosage adjustment is required.1

Renal Impairment

No dosage adjustment of osilodrostat phosphate in patients with impaired renal function is required. In patients with moderate to severe renal impairment, UFC levels should be interpreted with caution due to reduced UFC excretion.1

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). More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (incidence > 20%) are adrenal insufficiency, fatigue, nausea, headache, edema.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A4 Inhibitor: Reduce the dose of osilodrostat phosphate by half with concomitant use of a strong CYP3A4 inhibitor.1

  • CYP3A4 and CYP2B6 Inducers: An increase of osilodrostat phosphate dosage may be needed if osilodrostat phosphate is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in osilodrostat phosphate dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using osilodrostat phosphate.1

Actions

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).1

Advice to Patients

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Patient Information).1

Instruct patients on the importance of laboratory monitoring and adhering to their return visit schedule.1

Advise patients that osilodrostat phosphate is associated with hypocortisolism-related events. Advise patients to report symptoms of hypercortisolism to their healthcare provider.1

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.1

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.1

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.1

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.1

Advise females not to breastfeed during treatment with osilodrostat phosphate and for at least one week after treatment.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Osilodrostat Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, film-coated

1 mg (of osilodrostat)

Isturisa

Recordati Rare Diseases Inc.

5 mg (of osilodrostat)

Isturisa

Recordati Rare Diseases Inc.

10 mg (of osilodrostat)

Isturisa

Recordati Rare Diseases Inc.

AHFS Drug Information. © Copyright 2021, Selected Revisions April 13, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Recordati Rare Diseases, Inc. Isturisa (Osilodrostat) ORAL prescribing information. 2020 Mar http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a5ec24-63c3-4d83-b1c0-6c550fbe7ae2