Instructions for use and marketing status of levoketoconazole

1. Name:levoketoconazole, Recorlev, levoketoconazole (transliteration)

2. Indications:

Levoketoconazole is indicated for the treatment of endogenous hypercortisolism in adult patients with Cushing's syndrome in whom surgical treatment is not an option or is refractory.

Limitations of Use: Levoketoconazole is not approved for the treatment of fungal infections, and its safety and effectiveness have not been established.

3. Usage and dosage:

1. Laboratory testing before starting the drug:

(1) Obtain baseline liver tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin). Carefully consider the risks and potential benefits of initiating recovery in patients with AST or ALT above normal but ≤3 times the upper limit of normal.

(2) Obtain a baseline electrocardiogram (ECG).

(3) Correct hypokalemia and hypomagnesemia before initiating recovery.

2. Recommended dosage, titration and efficacy monitoring

Levoketoconazole starting dose150 mg orally twice daily with or without food. Titrate the dose to 150 mg daily, based on 24-hour urinary free cortisol levels and patient tolerance, no more frequently than every 2-3 weeks. Monitor cortisol levels on at least two 24-hour urinary cortisol collections every 2-3 weeks until an adequate clinical response is achieved. The maximum recommended dose is 1200 mg per day, 600 mg twice daily. If necessary for tolerability reasons, the dose may be reduced to 150 mg once daily. Once the maintenance dose is reached, monitor cortisol levels with at least two 24-hour urine-free cortisol collections every 1-2 months or as directed.

If 24-hour urinary free cortisol levels remain above the upper limit of normal despite treatment at the maximum recommended dose of 1200 mg per day, or if the patient is unable to tolerate treatment with levketoconazole, consider discontinuing levketoconazole and switching the patient to another therapy.

4. Adverse reactions:

In clinical studies of levoketoconazole, common adverse reactions include nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, liver injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory tract infection, myalgia, cardiac arrhythmia, back pain, insomnia/sleep disturbance, and peripheral edema. Levoketoconazole may cause serious adverse reactions, including hypocortisolism, allergic reactions, and decreased testosterone levels.

5. Supply and storage:

Levoketoconazole is available as150 mg x 50 tablets and can be stored at 20 to 25°C (68 to 77°F); excursions allowed between 15 to 30°C (59 to 86°F).

6. Taboo:

Levoketoconazole is contraindicated in the following patients

1. Suffering from cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, previous drug-induced liver injury due to treatment with ketoconazole or any azole antifungal drug requiring discontinuation of treatment, or extensive metastatic liver disease.

2. Take drugs that cause QT prolongation associated with ventricular arrhythmias (including torsade de pointes).

3. Baseline The QTcF interval is prolonged by more than 470 msec, and there is a history of torsade de pointes, ventricular fibrillation or long QT syndrome (including first-degree family history).

4. Known allergy to levoketoconazole, ketoconazole, or any of the excipients in RECORLEV.

5. Take certain drugs that are sensitive to CYP3A4 or CYP3A4 and P-gP.

7. Mechanism of action:

In vitro, levoketoconazole inhibits the key steps of cortisol and testosterone synthesis, mainly steps mediated byCYP11B1 (11β hydroxylase), CYP11A1 (cholesterol side chain cleavage enzyme, the first step in converting cholesterol to pregnenolone) and CYP17A1 (17α hydroxylase).

8. Listing situation:

In December 2021, levoketoconazole was approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States and is sold under the trade name Recorlev.

Reference materials:https://www.mayoclinic.org/drugs-supplements/levoketoconazole-oral-route/description/drg-20528328