RECORLEV Dosing for Cushing's Syndrome
The recommended starting dose of RECORLEV (levoketoconazole) is 150 mg orally twice daily, with dose titration by 150 mg daily increments no more frequently than every 2-3 weeks, up to a maximum of 1200 mg daily (600 mg twice daily). 1
Initial Dosing Protocol
- Start at 150 mg twice daily (total 300 mg/day), taken with or without food 1
- Obtain baseline liver function tests, ECG, and correct any hypokalemia or hypomagnesemia before initiating treatment 1
- This lower starting dose compared to ketoconazole racemate reflects levoketoconazole's greater potency as the active stereoisomer 2
Dose Titration Strategy
- Increase by 150 mg daily increments (e.g., 300 mg → 450 mg → 600 mg daily) 1
- Wait at least 2-3 weeks between dose increases to assess response and tolerability 1
- Maximum dose is 1200 mg daily, administered as 600 mg twice daily 1
- In the pivotal SONICS trial, doses ranged from 150 mg twice daily up to 600 mg twice daily during the 2-21 week titration phase 3
Monitoring for Efficacy
- Measure mean 24-hour urinary free cortisol (mUFC) as the primary marker of biochemical control 3
- Target normalization of mUFC (≤1.0 times upper limit of normal) 3
- In the SONICS study, 62 of 77 patients (81%) achieved mUFC normalization by end of dose titration 3
- Monitor serum cortisol levels to guide dose adjustments and avoid hypocortisolism 1, 4
- Assess clinical improvements in cardiovascular risk markers, body weight, blood pressure, and glucose metabolism 3, 2
Critical Safety Monitoring Requirements
Hepatotoxicity Surveillance
- Monitor liver enzymes (ALT, AST) before treatment and regularly during therapy 1
- Hepatotoxicity can be fatal; 10-11% of patients experienced ALT elevations >3× upper limit of normal in clinical trials 5, 3
- Discontinue immediately if ALT >3× upper limit of normal 1
- Most hepatotoxicity occurs within the first 6 months of treatment 5
Cardiac Monitoring
- Obtain baseline ECG and monitor QTc interval during treatment 1
- RECORLEV causes dose-related QT prolongation that can lead to torsades de pointes 1
- Contraindicated if baseline QTcF >470 msec or history of ventricular arrhythmias 1
- Two patients in SONICS developed QTcF >500 msec 3
Hypocortisolism Monitoring
- Watch for signs of adrenal insufficiency: fatigue, weakness, hypotension, hypoglycemia 1, 4
- Three patients in SONICS had suspected adrenal insufficiency 3
- Reduce dose or temporarily interrupt treatment if hypocortisolism develops 1
- Consider stress-dose steroids during illness or surgery 4
Contraindications and Drug Interactions
- Absolutely contraindicated with sensitive CYP3A4 substrates (e.g., certain statins, antiarrhythmics) 1
- Avoid proton pump inhibitors as levoketoconazole requires gastric acid for absorption 5
- Do not use with strong CYP3A4 inhibitors or inducers starting 2 weeks before and during treatment 1
- Use lowest possible atorvastatin dose (monitor if >20 mg daily) 1
- Monitor metformin patients closely for glycemic control and adjust dose as needed 1
Clinical Context and Limitations
- RECORLEV is indicated only when surgery is not an option or has failed 1
- In SONICS, 31% of patients maintained normalized mUFC at end of 6-month maintenance phase without dose increase 3
- Not approved for fungal infections despite structural similarity to ketoconazole 1
- Mean baseline mUFC in SONICS was 4.9× upper limit of normal, demonstrating efficacy in moderate-to-severe disease 3
- Most common adverse events (>20%): nausea (32%), headache (28%), hypokalemia, hemorrhage/contusion, hypertension 1, 3
Comparison to Ketoconazole Racemate
- Levoketoconazole is the 2S,4R stereoisomer with more potent steroidogenesis inhibition than the racemate 2
- For ketoconazole racemate in patients >12 years: start 400-600 mg/day divided 2-3 times, increase to 800-1200 mg/day, then maintain at 400-800 mg/day 6, 5
- The lower starting dose of RECORLEV (300 mg/day vs 400-600 mg/day) reflects its enhanced potency 1, 2