What is the recommended treatment plan, including dosage, for a patient with residual or recurrent Cushing's disease after surgery, using Isturisa (osilodrostat)?

Isturisa (Osilodrostat) for Cushing's Disease After Surgery

Isturisa (osilodrostat) is FDA-approved for treating adults with Cushing's disease who cannot undergo pituitary surgery or have persistent/recurrent disease after surgery, starting at 2 mg orally twice daily and titrating up to a maximum of 30 mg twice daily based on urinary free cortisol levels. 1

Patient Selection and Indications

Isturisa is specifically indicated for: 1

• Patients with persistent or recurrent Cushing's disease despite pituitary surgery
• De novo patients for whom surgery is not indicated or who have refused surgery
• Patients requiring medical therapy while awaiting or during radiotherapy 2

The drug targets adrenal steroidogenesis by inhibiting 11-β hydroxylase, thereby reducing cortisol production without directly addressing the pituitary tumor itself. 3

Dosing Protocol

Initial Dosing

Start with 2 mg orally twice daily (total 4 mg/day), taken with or without food. 1

Dose Titration Strategy

• Titrate at no greater than 2-week intervals based on mean 24-hour urinary free cortisol (mUFC) measurements 1
• Increase dose if mUFC remains above the upper limit of normal (ULN) 1
• Reduce dose if mUFC falls below the lower limit of normal (LLN) or if symptoms of hypocortisolism develop 1
• Maximum dose: 30 mg twice daily (60 mg/day total) 1

Dose Adjustments in Special Populations

• Moderate hepatic impairment: Start at 1 mg twice daily due to 1.44-fold increase in drug exposure 1
• Severe hepatic impairment: Start at 1 mg twice daily due to 2.66-fold increase in drug exposure 1
• Renal impairment: No dose adjustment required 1

Monitoring Requirements

Pre-Treatment Assessment

Obtain baseline electrocardiogram (ECG) to assess QT interval before initiating therapy, as osilodrostat can cause QT prolongation. 1, 3

Ongoing Monitoring

• ECG at 1 week after starting treatment and periodically thereafter 1
• 24-hour urinary free cortisol measurements to guide dose titration 1
• Serum potassium and magnesium levels to detect hypokalemia from elevated mineralocorticoid precursors 1, 3
• Blood pressure monitoring for hypertension 1, 3
• Assessment for signs of adrenal insufficiency (nausea, vomiting, fatigue, hypotension, abdominal pain) 1
• Evaluation for hyperandrogenic symptoms in females (hirsutism, acne) 1, 3

Clinical Efficacy Data

In the pivotal 48-week trial of 137 patients with persistent or recurrent Cushing's disease: 1

• 71 patients (52%) achieved mUFC normalization by Week 24 and were eligible for the randomized withdrawal phase
• 86% of patients maintained normal mUFC when continuing osilodrostat versus 29% on placebo during the 8-week withdrawal period
• Mean baseline mUFC was approximately 7× ULN (1006 nmol/24 hr)
• 88% of enrolled patients had undergone prior pituitary surgery 1

Beyond cortisol control, osilodrostat demonstrated improvements in glycemia, blood pressure, body weight, and quality of life parameters. 3

Critical Adverse Effects and Management

Hypocortisolism (Most Common)

Adrenal insufficiency is the most frequent adverse effect, requiring dose reduction or temporary discontinuation. 1, 3 Symptoms include nausea, vomiting, fatigue, hypotension, abdominal pain, and dizziness. 1

QT Prolongation

Assess cardiac medications and correct electrolyte disturbances before starting therapy. 1 Avoid concomitant use with other QT-prolonging drugs. 1, 3

Mineralocorticoid Excess

Elevation of adrenal hormone precursors (11-deoxycorticosterone) can cause: 1, 3

• Hypokalemia
• Hypertension
• Peripheral edema

Monitor potassium levels and treat with potassium supplementation or mineralocorticoid receptor antagonists as needed. 3

Hyperandrogenism in Females

Elevated androgen precursors may cause hirsutism, hypertrichosis, and acne. 1 Consider slower dose titration to minimize these effects. 3

Drug Interactions

Osilodrostat inhibits CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 enzymes, potentially increasing exposure to drugs metabolized by these pathways: 1

• 2.5-fold increase in caffeine exposure (CYP1A2)
• 1.9-fold increase in omeprazole exposure (CYP2C19)
• 1.5-fold increase in dextromethorphan exposure (CYP2D6)
• 1.5-fold increase in midazolam exposure (CYP3A4/5)

Review all concomitant medications, particularly cardiac drugs that may prolong QT interval. 1

Practical Recommendations for Clinical Use

Slower Titration Strategy

Consider a more gradual up-titration schedule (every 3-4 weeks instead of 2 weeks) to minimize adverse effects, particularly hyperandrogenic symptoms and electrolyte disturbances. 3

Combination Therapy Considerations

While osilodrostat monotherapy is effective, combination with other agents (e.g., cabergoline for visible tumors) may be rational when monotherapy fails, though this approach requires careful monitoring. 2

Role in Treatment Algorithm

Osilodrostat serves as second-line therapy after surgical failure, positioned alongside repeat surgery and radiotherapy. 4, 2 It is particularly valuable as:

• Bridge therapy while awaiting radiotherapy effects 4
• Long-term medical management when surgery/radiotherapy are contraindicated 4, 2
• Rapid cortisol control in severe disease 4

Contraception Considerations

Osilodrostat does not significantly impact oral contraceptive exposure (ethinyl estradiol/levonorgestrel), so standard contraceptive methods remain effective. 1

Breastfeeding

Advise patients not to breastfeed during treatment and for at least 1 week after discontinuation. 1

Common Pitfalls to Avoid

• Do not increase doses more frequently than every 2 weeks, as this increases risk of adverse effects without improving efficacy 1
• Do not ignore symptoms of hypocortisolism—these require immediate dose reduction or temporary discontinuation 1
• Do not forget to correct electrolyte abnormalities before initiating therapy, particularly in patients with cardiac risk factors 1
• Do not assume surgical cure assessment is reliable if patient received preoperative medical therapy, as HPA axis recovery during treatment may prevent postoperative adrenal insufficiency 4

Long-Term Follow-Up

Lifelong monitoring remains essential even with successful medical therapy, as Cushing's disease can recur up to 15 years after apparent control. 4, 2 Continue semi-annual clinical examination, 24-hour urinary free cortisol measurements, and morning serum cortisol for at least 2 years, followed by annual evaluation. 5, 2