Osilodrostat (Monograph)

Brand name: Isturisa
Drug 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: 928134-65-0

Medically reviewed by Drugs.com on Aug 12, 2022. Written by ASHP.

Introduction

Cortisol synthesis inhibitor.

Uses for Osilodrostat

Cushing Disease.

Treatment of Cushing disease in adults who are not candidates for pituitary surgery or in whom surgery was not curative.

Designated an orphan drug by FDA for use in this condition.

Treatment of choice for patients with Cushing disease is pituitary (transsphenoidal) surgery; osilodrostat is considered a second-line treatment option.

Osilodrostat Dosage and Administration

General

Pretreatment Screening

• Correct hypokalemia and hypomagnesemia prior to initiating osilodrostat therapy.

• Obtain a baseline ECG prior to initiating therapy.

Patient Monitoring

• Repeat ECG after 1 week of treatment and as clinically indicated thereafter. Consider more frequent ECG monitoring in patients with risk factors for QT prolongation (e.g., congenital long QT syndrome, congestive heart failure, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval).

• Monitor for hypokalemia and hypomagnesemia periodically during treatment; correct electrolyte abnormalities if indicated.

• During dosage titration, monitor cortisol levels from at least two 24-hour urine free cortisol collections every 1–2 weeks until adequate clinical response is maintained. Once maintenance dosage is achieved, monitor cortisol levels at least once every 1–2 months or as clinically indicated.

• More frequent monitoring of adrenal function may be required during dosage titration in patients with hepatic impairment.

Administration

Oral Administration

Administer orally without regard to food.

If a dose is missed, take next dose at the regularly scheduled time.

Dosage

Available as osilodrostat phosphate; dosage expressed in terms of osilodrostat.

Adults

Cushing Disease

Oral

Initially, 2 mg twice daily. Titrate dosage by 1–2 mg twice daily no more frequently than every 2 weeks based on rate of cortisol changes, individual tolerability, and improvement in signs and symptoms.

If patient tolerates a dosage of 10 mg twice daily and continues to have 24-hour urine free cortisol levels above the upper limit of normal, may further titrate dosage by 5 mg twice daily every 2 weeks up to maximum dosage of 30 mg twice daily.

Maintenance dosage in clinical trials ranged from 2–7 mg twice daily.

Dosage Modification for Toxicity

Reduce dosage or temporarily discontinue osilodrostat if urine free cortisol levels decrease below target range, cortisol levels rapidly decrease, and/or symptoms of hypocortisolism occur; initiate glucocorticoid replacement therapy if needed. Restart osilodrostat at a reduced dosage when cortisol levels return to target range and symptoms have resolved.

Prescribing Limits

Adults

Cushing Disease

Oral

Maximum 30 mg twice daily.

Special Populations

Hepatic Impairment

Cushing Disease

Oral

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate hepatic impairment (Child-Pugh class B): Initial dosage of 1 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Initial dosage of 1 mg once daily in the evening.

Renal Impairment

Cushing Disease

No dosage adjustment required.

Geriatric Patients

No dosage adjustment required in patients ≥65 years of age.

Cautions for Osilodrostat

Contraindications

• None.

Warnings/Precautions

Hypocortisolism

Risk of hypocortisolism and potentially life-threatening adrenal insufficiency. Manifestations may include nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.

Hypocortisolism can occur at any time during treatment. Evaluate patients for precipitating causes of hypocortisolism (e.g., infection, physical stress). Periodically monitor 24-hour urine free cortisol (UFC), serum or plasma cortisol, and signs/symptoms of hypocortisolism.

Reduce dosage or interrupt osilodrostat therapy if UFC levels fall below the target range, there is a rapid decrease in cortisol levels, and/or symptoms of hypocortisolism occur. If serum or plasma cortisol levels are below target range and symptoms of adrenal insufficiency are present, discontinue osilodrostat and initiate exogenous glucocorticoid replacement therapy. May restart drug at reduced dosage when UFC and serum or plasma cortisol levels are within target range, and/or symptoms have resolved.

QT Interval Prolongation

Dose-dependent QT interval prolongation reported; may cause cardiac arrhythmias.

Perform ECG to obtain a baseline QT_c interval measurement; monitor for drug effects on QT_c interval. Consider temporary discontinuance of osilodrostat if QT_c interval >480 msec.

Correct hypokalemia and/or hypomagnesemia prior to initiating osilodrostat, and periodically monitor potassium and magnesium concentrations during treatment; correct abnormalities as clinically indicated.

Use with caution in patients with risk factors for QT prolongation (e.g., congenital long QT syndrome, CHF, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval); consider more frequent ECG monitoring in such patients.

Elevations in Adrenal Hormone Precursors and Androgens

May increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens.

Risk of hypokalemia, edema, and hypertension. Correct hypokalemia prior to initiating therapy. During treatment, monitor for hypokalemia, worsening of hypertension, and edema. If hypokalemia occurs, treat with IV or oral potassium supplementation based on severity. If hypokalemia persists despite potassium supplementation, consider initiation of mineralocorticoid antagonists. Dosage reduction or discontinuance of osilodrostat may be necessary.

May cause hirsutism, hypertrichosis, and acne (in females).

Specific Populations

Pregnancy

No adequate data on developmental risks associated with use of osilodrostat in pregnant women.

Lactation

Not known whether osilodrostat is distributed into milk, affects milk production, or affects the breast-fed infant. Because of potential for serious adverse reactions (e.g., adrenal insufficiency) in the breast-fed infant, breast-feeding not recommended during treatment and for 1 week after the final dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Among 167 patients in clinical trials, 6% were ≥65 years of age; there were no patients >75 years of age. Manufacturer states that based on available data, no dosage adjustment required in patients ≥65 years of age.

Hepatic Impairment

Systemic exposure to osilodrostat is increased in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment; dosage adjustments recommended. Dosage adjustment not necessary in patients with mild hepatic impairment (Child-Pugh class A).

More frequent monitoring of adrenal function during dosage titration may be required in patients with hepatic impairment.

Renal Impairment

Renal impairment does not affect systemic exposure to osilodrostat; dosage adjustment not necessary.

Use caution in interpreting urine free cortisol levels in patients with moderate to severe renal impairment because of reduced urine free cortisol excretion.

Common Adverse Effects

Adverse effects (reported in ≥20% of patients): adrenal insufficiency, fatigue, nausea, headache, edema.

Drug Interactions

Metabolized via multiple CYP isoenzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and uridine diphosphate (UDP)-glucuronosyl transferases (UGT).

May inhibit CYP isoenzymes 1A2, 2C19, 2D6, and 3A4/5.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased concentrations and adverse effects of osilodrostat).

Potent inducers of CYP3A4 and/or CYP2B6: Potential pharmacokinetic interaction (decreased concentrations and efficacy of osilodrostat).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, CYP2C19, CYP2D6, or CYP3A4: Potential pharmacokinetic interaction (increased exposure of substrate drug).

Specific Drugs

Osilodrostat Pharmacokinetics

Absorption

Bioavailability

Increases in osilodrostat peak plasma concentrations and AUC slightly greater than dose-proportional over dose range of 1–30 mg.

Peak plasma concentrations achieved in approximately 1 hour.

Accumulation following multiple doses not observed.

Food

Administration of a single 30-mg dose with a high-fat meal reduces peak plasma concentrations and AUC by 11 and 21%, respectively, and delays time to peak plasma concentrations by 1–2.5 hours; effects not considered clinically important.

Special Populations

Bioavailability increased by approximately 20% in Asian patients compared with other ethnic groups; time to peak plasma concentrations and peak plasma concentrations also increased in Asian patients. Differences not considered clinically important.

Distribution

Plasma Protein Binding

36.4%.

Elimination

Metabolism

Extensively metabolized by multiple CYP isoenzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and UGTs, with no single enzyme being responsible for >25% of total clearance. Metabolites not considered pharmacologically active.

Elimination Route

Eliminated principally in urine (90.6%; 5.2% as unchanged drug). Minor amount (1.58%) eliminated in feces.

Half-life

Approximately 4 hours.

Special Populations

Osilodrostat systemic exposure increased by 1.44- or 2.66-fold in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, respectively.

Pharmacokinetics not substantially affected by renal impairment, age, sex, race, or body weight.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C); protect from moisture.

Actions

• Cortisol synthesis inhibitor; inhibits 11β-hydroxylase, enzyme responsible for final step of cortisol biosynthesis in adrenal gland.

• In patients with Cushing disease, osilodrostat causes a dose-dependent increase in levels of the cortisol precursor 11-deoxycortisol and corticotropin (ACTH).

Advice to Patients

• Importance of advising patients to read the FDA-approved patient labeling (patient information).

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

• Risk of hypocortisolism-related adverse events; importance of advising patients to report symptoms of hypocortisolism (e.g., anorexia, nausea, vomiting, abdominal pain, fatigue, hypotension, dizziness) to their clinician.

• Risk of QT interval prolongation; importance of advising patients of the signs and symptoms of QT interval prolongation (e.g., arrhythmia) and to contact their clinician immediately if such signs or symptoms occur.

• Advise patients of the importance of ECG monitoring before initiating treatment and periodically thereafter. Advise patients with risk factors for QT-interval prolongation that adjustments in cardiac medications and correction of electrolyte disturbances may be necessary.

• Risk of elevation of adrenal hormone precursors, possibly leading to hypokalemia, worsening of hypertension, and edema; importance of patients reporting these symptoms to their clinician.

• Risk of elevated androgen levels, possibly leading to hirsutism, hypertrichosis, and acne (in females); importance of patients reporting these symptoms to their clinician.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise females not to breast-feed during treatment with osilodrostat and for at least 1 week after discontinuance of treatment.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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 is obtained through a speciality distributor. Contact the manufacturers website for additional information.

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