Recorlev

RECORLEV- levoketoconazole tablet
Xeris Pharmaceuticals, Inc.

WARNING: HEPATOTOXICITY AND QT PROLONGATION

Hepatotoxicity

• Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV [see Warnings and Precautions (5.1)].

• RECORLEV is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease [see Contraindications (4), Warnings and Precautions (5.1)].

• Evaluate liver enzymes prior to and during treatment. Interrupt RECORLEV treatment immediately if signs of hepatotoxicity occur [see Dosage and Administration (2.1, 2.3, 2.4), Warnings and Precautions (5.1)].

QT Prolongation
• RECORLEV is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias such as torsades de pointes [see Warnings and Precautions (5.2)].

• Coadministration of RECORLEV with other drugs that prolong the QT interval associated with ventricular arrhythmias, including torsades de pointes, and use in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) are contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.2)].

• Perform an ECG and correct hypokalemia and hypomagnesemia prior to and during treatment. Temporarily discontinue RECORLEV if QTcF interval exceeds 500 msec [Dosage and Administration (2.1, 2.3, 2.4)].

1 INDICATIONS AND USAGE

RECORLEV is 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.


Limitations of Use

RECORLEV is not approved for the treatment of fungal infections. The safety and effectiveness of RECORLEV for the treatment of fungal infections have not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Laboratory Testing Prior to RECORLEV Initiation

  • Obtain baseline liver tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin]. Carefully consider the risks and potential benefits of initiating RECORLEV in patients with AST or ALT above normal but less than or equal to 3 times the upper limit of normal [see Contraindications (4), Warnings and Precautions (5.1)].
  • Obtain baseline electrocardiogram (ECG) [see Contraindications (4), Warnings and Precautions (5.2)].
  • Correct hypokalemia and hypomagnesemia prior to starting RECORLEV [see Warnings and Precautions (5.2)].

2.2 Recommended Dosage, Titration, and Monitoring for Efficacy

  • Initiate dosage at 150 mg orally twice daily, with or without food [see Clinical Pharmacology (12.3)].
  • Titrate the dosage by 150 mg daily, no more frequently than every 2-3 weeks based on 24-hour urine free cortisol levels and patient tolerability [see Dosage and Administration (2.4)]. Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 2-3 weeks until an adequate clinical response is achieved.
  • The maximum recommended dosage is 1200 mg per day, administered as 600 mg twice daily.
  • The dosage may be reduced to 150 mg once daily if needed for reasons of tolerability [see Dosage and Administration (2.3, 2.4)].
  • 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.

2.3 Monitoring for Safety

Perform the following monitoring during RECORLEV treatment. Refer to Dosage Interruptions and Modifications below for recommendations pertaining to management of liver, cortisol, or ECG abnormalities [see Dosage and Administration (2.4)].

Hepatotoxicity

  • Serious hepatotoxicity has been reported in patients receiving RECORLEV, and therefore frequent monitoring of liver tests is recommended.
  • Monitor liver enzymes and bilirubin weekly for at least 6 weeks after starting RECORLEV, every 2 weeks for the next 6 weeks, monthly for the next 3 months, and then as clinically indicated.
  • After any dose interruption or dose increase, monitor on a weekly basis until a stable dosage is achieved [see Warnings and Precautions (5.1)].

QT Prolongation

  • Conduct an ECG before each dose increase. After a stable dosage is established, monitor routinely for an effect on the QT interval.
  • Monitor blood potassium and magnesium levels periodically during treatment [see Warnings and Precautions (5.2)].

Hypocortisolism

  • Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism periodically during RECORLEV treatment [see Warnings and Precautions (5.3)].

2.4 Dosage Interruptions and Modifications

Hepatotoxicity

Refer to Table 1 for management of hepatotoxicity [see Warnings and Precautions (5.1) ].

Table 1: Dosage Modification and Management for Hepatotoxicity
ALT or AST

Total Bilirubin

Recommendation

≥ 5 x ULN

Any value

Permanently discontinue RECORLEV.

≥ 3 x ULN

> 2 x ULN

Permanently discontinue RECORLEV.

≥ 3 to < 5 x ULN

≤ 2 x ULN

  • Temporarily discontinue RECORLEV.
  • Monitor liver tests every 3 days until the levels are stable, and then no less than every 7 to 10 days until tests have returned to baseline levels.
  • RECORLEV may be restarted at a lower dosage and titrated more slowly once liver tests normalize, and other possible contributing factors have been addressed. Before considering a dosage increase, monitor liver tests weekly for 1 month and then routinely thereafter.
  • Permanently discontinue RECORLEV if a liver test abnormality significantly above the patient’s baseline recurs after restarting RECORLEV.

> ULN to <3 x ULN

Any value

  • If liver tests increase above the patient’s baseline, monitor liver tests no less than every 7 to 10 days until tests have returned to baseline levels. Consider temporary discontinuation of RECORLEV during this time.
  • If RECORLEV is discontinued, restart at a lower dosage and titrate more slowly once liver tests return to baseline and other possible contributing factors have been addressed. Before considering a dosage increase, monitor liver tests weekly for 1 month to ensure stability of liver tests.

QT Prolongation

  • Temporarily discontinue RECORLEV if the QTcF interval is longer than 500 msec.
  • After correction of other possible contributing factors (e.g., hypokalemia, hypomagnesemia, use of concomitant drugs), RECORLEV may be resumed at a lower dosage when the QTcF interval returns to 500 msec or less.
  • If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV [see Warnings and Precautions (5.2)].

Hypocortisolism

  • Decrease the dosage or temporarily discontinue RECORLEV if urine free cortisol or morning serum or plasma cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, or if signs and/or symptoms consistent with hypocortisolism are reported.
  • Stop RECORLEV and administer exogenous glucocorticoid replacement therapy if morning serum or plasma cortisol levels are below target range and signs and/or symptoms of adrenal insufficiency or hypocortisolism are present.
  • Re-initiate RECORLEV at a lower dosage when cortisol levels are within target ranges and signs and/or symptoms of hypocortisolism have resolved [ see Warnings and Precautions (5.3)]. The dosage may be titrated to the previous dose associated with hypocortisolism if the reduced dosage has been well tolerated and the reduced dosage does not achieve an adequate clinical response.

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