What is mechanism of action?

mechanism of action is P-Glycoprotein Inhibitors [MoA], Cytochrome P450 3A4 Inhibitors [MoA], Cytochrome P450 11B1 Inhibitors [MoA], Cytochrome P450 2B6 Inhibitors [MoA], Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA], Cytochrome P450 17A1 Inhibitors [MoA], Cytochrome P450 2C8 Inhibitors [MoA], Cytochrome P450 11A1 Inhibitors [MoA] or Organic Cation Transporter 2 Inhibitors [MoA]

Recorlev (levoketoconazole) - Complete Medication Label Info, PA Forms, & Patient Education (2025)

Recorlev Prescribing Information

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 Hepatotoxicity

Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV.

RECORLEV is contraindicated in patients with 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, 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 ]

.

Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV

[see Drug Interactions ]

.

Prompt recognition of liver injury is essential. At baseline, obtain liver tests

[see Dosage and Administration ]

. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration

[see Dosage and Administration ]

.

Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal.

Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified

[see Dosage and Administration ].

For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications

[see Dosage and Administration ]

. If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.

)].

• 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 CONTRAINDICATIONS

RECORLEV is contraindicated in patients:

With 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, 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 Warnings and Precautions ]
.
Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
[see Warnings and Precautions ]
.
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)
[see Warnings and Precautions ]
.
With known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV
[see Warnings and Precautions , Adverse Reactions ]
.
Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gP
[see Drug Interactions ]
.

Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, 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
Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome
Hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV
Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp

), Warnings and Precautions (

5.1 Hepatotoxicity

Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV.

RECORLEV is contraindicated in patients with 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, 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 ]

.

Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV

[see Drug Interactions ]

.

Prompt recognition of liver injury is essential. At baseline, obtain liver tests

[see Dosage and Administration ]

. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration

[see Dosage and Administration ]

.

Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal.

Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified

[see Dosage and Administration ].

For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications

[see Dosage and Administration ]

. If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.

)].

• Evaluate liver enzymes prior to and during treatment. Interrupt RECORLEV treatment immediately if signs of hepatotoxicity occur

[see 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 , Warnings and Precautions ].
Obtain baseline electrocardiogram (ECG)
[see Contraindications , Warnings and Precautions ].
Correct hypokalemia and hypomagnesemia prior to starting RECORLEV
[see Warnings and Precautions ].

,

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 ].

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 ].

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 ].

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 ].

,

2.4 Dosage Interruptions and Modifications

Hepatotoxicity

Refer to Table 1for management of hepatotoxicity

[see Warnings and Precautions

]

.

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 ]
.

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 ]
. 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.

), Warnings and Precautions (

5.1 Hepatotoxicity

Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV.

RECORLEV is contraindicated in patients with 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, 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 ]

.

Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV

[see Drug Interactions ]

.

Prompt recognition of liver injury is essential. At baseline, obtain liver tests

[see Dosage and Administration ]

. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration

[see Dosage and Administration ]

.

Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal.

Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified

[see Dosage and Administration ].

For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications

[see Dosage and Administration ]

. If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.

)].

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 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. During Studies 1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities.

RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes

[see Drug Interactions ]

.

RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated 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)

[see Contraindications , Drug Interactions ].

Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered.

Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment

[see Dosage and Administration ]

. Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV

[see Dosage and Administration ]

.

)].

• 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 CONTRAINDICATIONS

RECORLEV is contraindicated in patients:

With 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, 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 Warnings and Precautions ]
.
Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
[see Warnings and Precautions ]
.
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)
[see Warnings and Precautions ]
.
With known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV
[see Warnings and Precautions , Adverse Reactions ]
.
Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gP
[see Drug Interactions ]
.

Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, 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
Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome
Hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV
Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp

), Drug Interactions (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

,

7.2 Effect of Other Drugs on RECORLEV

Table 7presents clinically significant drug interactions that affect RECORLEV.

Table 7: Clinically Significant Drug Interactions (Drugs that Affect RECORLEV)
Strong CYP3A4 Inhibitors
Clinical Impact	May increase plasma concentrations of levoketoconazole and increase the risk of adverse reactions from RECORLEV [see Clinical Pharmacology ] .
Prevention or Management	Administration of strong enzyme inhibitors of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) Glucocorticoid and progesterone receptor antagonists (e.g., mifepristone)
Strong CYP3A4 Inducers
Clinical Impact	May decrease plasma concentrations of levoketoconazole and reduce the efficacy of RECORLEV
Prevention or Management	Administration of strong enzyme inducers of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antibacterials (e.g., isoniazid, rifabutin, rifampicin) Anticonvulsants (e.g., carbamazepine, phenytoin) Antivirals (e.g., efavirenz, nevirapine) Cytotoxic agents (e.g., mitotane)
Gastric Acid Neutralizers
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Take gastric acid neutralizers a minimum of 2 hours after dosing with RECORLEV.
Examples	Aluminum hydroxide
Gastric Acid Suppressors
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of gastric acid suppressors with RECORLEV.
Examples	H2-receptor antagonists and proton pump inhibitors
Sucralfate
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of sucralfate with RECORLEV.

)].

• 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 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 , Warnings and Precautions ].
Obtain baseline electrocardiogram (ECG)
[see Contraindications , Warnings and Precautions ].
Correct hypokalemia and hypomagnesemia prior to starting RECORLEV
[see Warnings and Precautions ].

,

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 ].

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 ].

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 ].

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 ].

,

2.4 Dosage Interruptions and Modifications

Hepatotoxicity

Refer to Table 1for management of hepatotoxicity

[see Warnings and Precautions

]

.

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 ]
.

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 ]
. 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.

)].

RECORLEV is contraindicated in patients:

With 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, 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 Warnings and Precautions (

5.1 Hepatotoxicity
Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV.
RECORLEV is contraindicated in patients with 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, 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 ]
.
Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV
[see Drug Interactions ]
.
Prompt recognition of liver injury is essential. At baseline, obtain liver tests
[see Dosage and Administration ]
. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration
[see Dosage and Administration ]
.
Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal.
Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified
[see Dosage and Administration ].
For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications
[see Dosage and Administration ]
. If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.
)]

.
Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes

[see Warnings and Precautions (

5.2 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. During Studies 1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities.
RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes
[see Drug Interactions ]
.
RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated 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)
[see Contraindications , Drug Interactions ].
Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered.
Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment
[see Dosage and Administration ]
. Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV
[see Dosage and Administration ]
.
)]

.
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)

[see Warnings and Precautions (

5.2 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. During Studies 1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities.
RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes
[see Drug Interactions ]
.
RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated 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)
[see Contraindications , Drug Interactions ].
Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered.
Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment
[see Dosage and Administration ]
. Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV
[see Dosage and Administration ]
.
)]

.
With known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV

[see Warnings and Precautions (

5.4 Hypersensitivity Reactions
Hypersensitivity reactions have been reported in 1% of patients treated with RECORLEV in the clinical trials
[see Adverse Reactions ]
.
Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole
[see Adverse Reactions ].
RECORLEV is contraindicated in patients with a known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV.
), Adverse Reactions (

6.2 Postmarketing Experience
The following adverse reactions have been identified from published reports or postmarketing experience with ketoconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ketoconazole exposure.
Blood and Lymphatic System Disorders
: thrombocytopenia
Endocrine Disorders:
adrenocortical insufficiency
Hepatobiliary Disorders:
serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death
Immune System Disorders:
allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema
Nervous System Disorders:
reversible intracranial pressure increased (e.g., papilledema, fontanelle bulging in infants)
Reproductive System and Breast Disorders:
erectile dysfunction; with dosages higher than 200 or 400mg daily, azoospermia.
Skin and Subcutaneous Tissue Disorders:
acute generalized exanthematous pustulosis, photosensitivity
)]

.

Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gP

[see Drug Interactions (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

)]

.

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hepatotoxicity

[see Warnings and Precautions (

5.1 Hepatotoxicity
Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV.
RECORLEV is contraindicated in patients with 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, 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 ]
.
Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV
[see Drug Interactions ]
.
Prompt recognition of liver injury is essential. At baseline, obtain liver tests
[see Dosage and Administration ]
. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration
[see Dosage and Administration ]
.
Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal.
Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified
[see Dosage and Administration ].
For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications
[see Dosage and Administration ]
. If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.
)]
QT Prolongation

[see Warnings and Precautions (

5.2 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. During Studies 1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities.
RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes
[see Drug Interactions ]
.
RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated 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)
[see Contraindications , Drug Interactions ].
Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered.
Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment
[see Dosage and Administration ]
. Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV
[see Dosage and Administration ]
.
)]
Hypocortisolism

[see Warnings and Precautions (

5.3 Hypocortisolism
RECORLEV lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Adrenal insufficiency was observed in 7% of patients during the clinical program of RECORLEV
[see Adverse Reactions ]
. Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism may occur at any time during RECORLEV treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms periodically during RECORLEV treatment
[see Dosage and Administration ]
.
Decrease the dosage or temporarily discontinue RECORLEV if urine free cortisol or morning blood 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
[see Dosage and Administration ]
.
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. After RECORLEV discontinuation, cortisol suppression may persist beyond the 4- to 6- hour half-life of RECORLEV.
If treatment is interrupted due to hypocortisolism, re-initiate RECORLEV at a lower dosage when cortisol levels are within target ranges and patient’s signs and/or symptoms have resolved
[see Dosage and Administration ]
. 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.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
)]
Hypersensitivity Reactions

[see Warnings and Precautions (

5.4 Hypersensitivity Reactions
Hypersensitivity reactions have been reported in 1% of patients treated with RECORLEV in the clinical trials
[see Adverse Reactions ]
.
Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole
[see Adverse Reactions ].
RECORLEV is contraindicated in patients with a known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV.
)]
Risks related to Decreased Testosterone

[see Warnings and Precautions (

5.5 Risks Related to Decreased Testosterone
RECORLEV may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes. Inform patients of the symptoms associated with low testosterone levels and advise patients to contact a healthcare provider if they occur.
)]

Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating RECORLEV (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

)

Sensitive CYP3A4 or CYP3A4 and P-gp Substrates

: Concomitant use of RECORLEV with these substrates is contraindicated or not recommended (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

)

Atorvastatin

: Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

)

Metformin

: Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed (

7.1 Effect of RECORLEV on Other Drugs

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs.

Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV.

Table 6presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use. It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin.

Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates
^aThe drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug. Consult the approved product labeling for the substrate drug for more information. ^bStrong CYP3A4 inhibitor [see Drug Interactions ] . ^cBased on clinical drug interaction study with levoketoconazole.
CYP3A4 or CYP3A4 and P-gp Substrates^aThat May Prolong QT
Clinical Impact	Increases risk of QT prolongation and torsades de pointes.
Prevention or Management	Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated [see Contraindications , Warnings and Precautions ].
Examples	Bosutinib, cisapride, clarithromycin^b,cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine.
Sensitive CYP3A4 or CYP3A4 and P-gp Substrates^a
Clinical Impact	Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions.
Prevention or Management	Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended [see Contraindications ] . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptan^b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir^b, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin^c
Clinical Impact	Increases plasma concentration of atorvastatin^cand may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis [see Clinical Pharmacology ] .
Prevention or Management	Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily .
OCT2 and MATE Substrate Metformin^c
Clinical Impact	Increases plasma concentration of metformin^cand may increase the risk of metformin’s adverse reactions [see Clinical Pharmacology ] . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions .
Prevention or Management	During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.

)

Strong CYP3A4 Inhibitors or Inducers

: Avoid use of these drugs 2 weeks before and during RECORLEV treatment (

7.2 Effect of Other Drugs on RECORLEV

Table 7presents clinically significant drug interactions that affect RECORLEV.

Table 7: Clinically Significant Drug Interactions (Drugs that Affect RECORLEV)
Strong CYP3A4 Inhibitors
Clinical Impact	May increase plasma concentrations of levoketoconazole and increase the risk of adverse reactions from RECORLEV [see Clinical Pharmacology ] .
Prevention or Management	Administration of strong enzyme inhibitors of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) Glucocorticoid and progesterone receptor antagonists (e.g., mifepristone)
Strong CYP3A4 Inducers
Clinical Impact	May decrease plasma concentrations of levoketoconazole and reduce the efficacy of RECORLEV
Prevention or Management	Administration of strong enzyme inducers of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antibacterials (e.g., isoniazid, rifabutin, rifampicin) Anticonvulsants (e.g., carbamazepine, phenytoin) Antivirals (e.g., efavirenz, nevirapine) Cytotoxic agents (e.g., mitotane)
Gastric Acid Neutralizers
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Take gastric acid neutralizers a minimum of 2 hours after dosing with RECORLEV.
Examples	Aluminum hydroxide
Gastric Acid Suppressors
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of gastric acid suppressors with RECORLEV.
Examples	H2-receptor antagonists and proton pump inhibitors
Sucralfate
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of sucralfate with RECORLEV.

)

Gastric Acid Modulators

: See Full Prescribing Information for recommendations regarding concomitant use with RECORLEV (

7.2 Effect of Other Drugs on RECORLEV

Table 7presents clinically significant drug interactions that affect RECORLEV.

Table 7: Clinically Significant Drug Interactions (Drugs that Affect RECORLEV)
Strong CYP3A4 Inhibitors
Clinical Impact	May increase plasma concentrations of levoketoconazole and increase the risk of adverse reactions from RECORLEV [see Clinical Pharmacology ] .
Prevention or Management	Administration of strong enzyme inhibitors of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) Glucocorticoid and progesterone receptor antagonists (e.g., mifepristone)
Strong CYP3A4 Inducers
Clinical Impact	May decrease plasma concentrations of levoketoconazole and reduce the efficacy of RECORLEV
Prevention or Management	Administration of strong enzyme inducers of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV.
Examples	Antibacterials (e.g., isoniazid, rifabutin, rifampicin) Anticonvulsants (e.g., carbamazepine, phenytoin) Antivirals (e.g., efavirenz, nevirapine) Cytotoxic agents (e.g., mitotane)
Gastric Acid Neutralizers
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Take gastric acid neutralizers a minimum of 2 hours after dosing with RECORLEV.
Examples	Aluminum hydroxide
Gastric Acid Suppressors
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of gastric acid suppressors with RECORLEV.
Examples	H2-receptor antagonists and proton pump inhibitors
Sucralfate
Clinical Impact	Impairs absorption of levoketoconazole from RECORLEV.
Prevention or Management	Avoid use of sucralfate with RECORLEV.

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