What monitoring and safety precautions are required when initiating osilodrostat (ISTURISA) for Cushing disease?

Monitoring and Safety Precautions When Prescribing Osilodrostat

When prescribing osilodrostat for Cushing disease, you must systematically monitor for hypocortisolism, hypokalemia, QTc prolongation, and hyperandrogenic effects, with baseline assessments and regular follow-up during dose titration being critical to prevent life-threatening complications. 1

Pre-Treatment Baseline Assessment

Before initiating osilodrostat, obtain the following mandatory baseline evaluations:

• Electrocardiogram (ECG) to measure baseline QTc interval, as osilodrostat causes dose-dependent QT prolongation (up to 5.3 ms at 30 mg) 1
• Serum potassium and magnesium levels must be checked and corrected if abnormal, since hypokalemia occurs in 42% of patients due to mineralocorticoid precursor accumulation 2, 3, 1
• Blood pressure measurement to establish baseline, as mineralocorticoid excess frequently causes hypertension alongside hypokalemia 3, 1
• 24-hour urinary free cortisol (UFC) and serum/plasma cortisol levels to establish baseline hypercortisolism severity 1, 4

Critical Monitoring During Treatment

Hypocortisolism Surveillance (Highest Priority)

• Monitor 24-hour UFC, serum/plasma cortisol, and clinical symptoms periodically throughout treatment, as hypocortisolism can occur at any time and may be life-threatening 1
• Hypocortisolism-related adverse events occur in 27-51% of patients, most commonly during the initial dose-titration period (weeks 1-12) 2, 1, 4
• Watch for symptoms of adrenal insufficiency: nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness, hypotension, abnormal electrolytes, and hypoglycemia 1
• Decrease or temporarily discontinue osilodrostat if UFC falls below target range, there is rapid cortisol decrease, or symptoms of hypocortisolism appear 1
• Stop osilodrostat and administer exogenous glucocorticoid replacement if serum/plasma cortisol is below target and patient has adrenal insufficiency symptoms 1
• Cortisol suppression may persist beyond the 4-hour half-life after discontinuation, requiring continued vigilance 1

Electrolyte and Cardiovascular Monitoring

• Check serum potassium every 1-2 weeks during dose titration to detect early hypokalemia from mineralocorticoid precursor accumulation (11-deoxycorticosterone) 3, 5
• Hypokalemia must be corrected prior to initiating osilodrostat and treated promptly if it develops during therapy 5, 1
• Administer potassium supplementation (intravenous or oral based on severity) when serum potassium falls below normal range 3, 1
• Consider adding mineralocorticoid antagonists (e.g., spironolactone) if hypokalemia persists despite potassium supplementation 5, 1
• Perform periodic ECGs to monitor for QTc prolongation, especially in patients with risk factors (congenital long QT syndrome, heart failure, bradyarrhythmias, concomitant QT-prolonging medications) 1, 6
• Consider temporary discontinuation if QTc interval exceeds 480 ms 1
• Monitor blood pressure regularly for worsening hypertension and edema from mineralocorticoid effects 3, 1

Hyperandrogenic Effects (Especially in Females)

• Monitor for hirsutism, hypertrichosis, and acne in female patients, as androgen accumulation occurs from 11β-hydroxylase blockade 2, 1
• Inform patients about hyperandrogenic symptoms and advise them to report these effects promptly 1
• Dose reduction or discontinuation may be necessary if hyperandrogenic effects become intolerable 1

Common Pitfalls to Avoid

• Do not confuse osilodrostat with potassium-sparing agents—osilodrostat causes hypokalemia (not hyperkalemia) through mineralocorticoid precursor accumulation, the opposite effect of spironolactone 3
• Do not rely solely on cortisol immunoassays—11-deoxycortisol may produce clinically relevant cross-reactivity with cortisol in both blood and urine immunoassays, potentially masking true hypocortisolism 2
• Do not overlook drug-drug interactions—carefully assess concomitant medications that prolong QT interval and consider more frequent ECG monitoring 1, 6
• Do not use aggressive up-titration—slower dose escalation minimizes adverse effects, particularly adrenal insufficiency 6

Dosing Strategy

• Start at 2 mg twice daily in most patients (used in 64.3% of real-world cases), with adjustments every 2 weeks based on UFC levels and tolerability 7, 4
• Maximum dose is 30 mg twice daily, though most patients respond at lower doses (median maintenance dose 2 mg twice daily in 66.7% of responders) 7, 4
• Response occurs rapidly—median UFC normalization achieved within 2 weeks in first-line monotherapy patients 8
• Consider block-and-replace strategy (higher osilodrostat dose with glucocorticoid replacement) if titration approach proves difficult 8

Evidence Quality

These recommendations are derived from FDA labeling 1, high-quality Lancet Diabetes & Endocrinology guidelines 2, 3, and pivotal Phase III trial data 4, representing Level A evidence.