General Information

Recorlev (levoketoconazole) is a cortisol synthesis inhibitor.

Recorlev is specifically indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

Recorlev is supplied as tablets for oral administration. 

Obtain baseline liver and electrocardiogram tests and correct hypokalemia and hypomagnesemia before starting Recorlev. Initiate dosage at 150 mg orally twice daily, with or without food. Titrate dosage by 150 mg daily, no more frequently than every 2-3 weeks. Maximum recommended dosage is 1200 mg daily, administered as 600 mg twice daily. Once the maintenance dosage is achieved, monitor cortisol levels from at least two 24-hour urine free cortisol collections at least every 1-2 months or as indicated. If 24-hour urine free cortisol levels remain above the upper normal limit after treatment with the maximum recommended dosage of 1200 mg per day, or the patient cannot tolerate treatment with Recorlev, consider discontinuing Recorlev and switching patient to another therapy.

Mechanism of Action

Recorlev (levoketoconazole) is a cortisol synthesis inhibitor. In vitro, levoketoconazole inhibits key steps in the synthesis of cortisol and testosterone, principally those mediated by CYP11B1 (11β hydroxylase), CYP11A1 (the cholesterol side-chain cleavage enzyme, the first step in the conversion of cholesterol to pregnenolone), and CYP17A1 (17α-hydroxylase).

Side Effects

Adverse effects associated with the use of Recorlev may include, but are not limited to, the following:

• nausea/vomiting
• hypokalemia
• hemorrhage/contusion
• systemic hypertension
• headache
• hepatic injury
• abnormal uterine bleeding
• erythema
• fatigue
• abdominal pain/dyspepsia
• arthritis
• upper respiratory infection
• myalgia
• arrhythmia
• back pain
• insomnia/sleep disturbances
• peripheral edema

The Recorlev drug label comes with the following Black Box Warning: Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. Recorlev is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment. Recorlev is associated with dose-related QT interval prolongation. QT interval prolongation may result in lifethreatening ventricular dysrhythmias such as torsades de pointes. Perform ECG prior to and during treatment.

Clinical Trial Results

The approval of Recorlev was based upon safety and efficacy data from two positive Phase 3 studies, SONICS and LOGICS. The studies evaluated a combined study population of 166 patients, which was representative of the adult drug-treated U.S. population with Cushing’s syndrome.

The open-label, single-arm SONICS study achieved statistical significance of its pre-specified primary endpoint, with 30% of patients achieving normalization of mean urinary free cortisol (UFC) following six months of maintenance treatment with Recorlev without a dose increase. For key secondary endpoints of cardiovascular risk, including fasting blood glucose, hemoglobin A1C, total cholesterol, low density lipoprotein (LDL)-cholesterol, body weight and body mass index (BMI), Recorlev demonstrated statistically significant and clinically meaningful improvements from baseline.

LOGICS was a double-blind, placebo-controlled randomized-withdrawal study. At the end of the randomized-withdrawal phase, 54.5% more patients who were withdrawn to placebo had a loss of mean urinary free cortisol (mUFC) response as compared with those who remained on Recorlev (95.5% vs 40.9% percent respectively). All 21 patients who lost response after being randomized to placebo received early rescue treatment within the 8-week randomized-withdrawal phase with a median time to early rescue of 22 days. The secondary endpoint of normalization of mUFC at the end of the randomized-withdrawal phase was also highly statistically significant with 45.5% more patients treated with Recorlev maintaining mUFC normalization in the active arm than the placebo arm (50% vs 4.5% respectively).