Contents

RECORLEV (levoketoconazole) tablets

RECORLEV (levoketoconazole) tablets contain levoketoconazole as the active ingredient. Levoketoconazole is the 2S,4R-enantiomer derived from racemic ketoconazole and is a cortisol synthesis inhibitor.

The chemical name of levoketoconazole is 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1ylmethyl)-1,3-dioxolan-4-yl] methoxyl]phenyl] piperazine.

The molecular formula of levoketoconazole is C₂₆H₂₈C_l2N₄O₄ with a molecular mass of 531.43 g/mol.

Levoketoconazole is a white or almost white crystalline powder. It is very slightly soluble in water but soluble in aqueous solutions below pH 2.

RECORLEV tablets for oral administration contain 150 mg of levoketoconazole and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, modified corn starch, and silicified microcrystalline cellulose. The non-functional pink film-coating contains iron oxide red, macrogol/polyethylene glycol 3350, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide. The tablets are printed with a black imprinting ink that contains ammonium hydroxide 28%, ferrosoferric oxide, isopropyl alcohol, propylene glycol, and shellac glaze 45% (20% esterified) in ethanol.

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.

Mechanism of Action

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).

DOSAGE AND ADMINISTRATION

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.
Obtain baseline electrocardiogram (ECG).
Correct hypokalemia and hypomagnesemia prior to starting RECORLEV.

Recommended Dosage, Titration, and Monitoring for Efficacy

Initiate dosage at 150 mg orally twice daily, with or without food.
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. 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.
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.

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.

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.

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.

Hypocortisolism

Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism periodically during RECORLEV treatment

Dosage Interruptions and Modifications

Hepatotoxicity: Refer to Table 1 for management of hepatotoxicity

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.

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. 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.

Missed Dose

If a dose of RECORLEV is missed, the patient should take the next dose at the regularly scheduled time.

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

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.

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

Prompt recognition of liver injury is essential. At baseline, obtain liver tests. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration.

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.

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 hepatoxicity with RECORLEV dosage interruption or modifications [see Dosage and Administration (2.4)]. 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. 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.

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).

Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrythmias, 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. 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.

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. 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.

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.

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. 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: Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole.

RECORLEV is contraindicated in patients with a known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV.

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.

DRUG INTERACTIONS

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 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates

CYP3A4 or CYP3A4 and P-gp Substratesa That 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
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 Substratesa
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 . Refer to the prescribing information of the substrate drug.
Examples	Alfentanil, avanafil, buspirone, conivaptanb , dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavirb, triazolam, and vardenafil.
CYP3A4 Substrate Atorvastatin c
Clinical Impact	Increases plasma concentration of atorvastatin c and may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis .
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 c and may increase the risk of metformin’s adverse reactions. 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.

^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.

^cBased on clinical drug interaction study with levoketoconazole.

Effect of Other Drugs on 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.
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

Alcohol: Patients should be advised against excessive alcohol consumption while using RECORLEV. When used with alcohol cases of a disulfiram-like reaction have been reported with ketoconazole characterized by flushing, rash, peripheral edema, nausea, and headache. All symptoms completely resolved within a few hours.

USE IN SPECIFIC POPULATIONS

Pregnancy: Levoketoconazole is the 2S, 4R enantiomer of ketoconazole. The available published data from case series and case-control studies on the use of the racemic ketoconazole during pregnancy are insufficient to determine a drug-associated risk of major birth defects. There are no available data on ketoconazole use during pregnancy to inform the risk of miscarriage. There are risks to the mother and fetus from untreated Cushing’s syndrome. No animal reproduction studies have been performed with levoketoconazole. However, levoketoconazole constituted about 70% of the exposure in humans and animals after racemic ketoconazole administration. In animal reproduction studies, embryotoxic effects were observed in pregnant mice, rats and rabbits, and fetal malformations were observed in rats, following oral dosing of racemic ketoconazole during the period of organogenesis at doses equal and less than the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus and consider whether the benefits of treatment with RECORLEV outweigh the risks.

Active Cushing’s syndrome during pregnancy has been associated with an increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, pre-eclampsia, maternal death, miscarriage, intrauterine fetal demise, preterm birth and neonatal death).

Lactation: Published data from one lactating woman show that ketoconazole is present in human milk in low amounts, with no reported adverse effects on the breastfed infant. However, these limited data are not sufficient to inform the risk to a breastfed infant with exposure to ketoconazole through breast milk. There are no data available on the effects of ketoconazole on milk production. Because of the potential for serious adverse reactions in the breastfed infant, including liver toxicity, advise patients not to breastfeed during treatment with RECORLEV and for one day (5 times the half-life) after the final dose.

Females and Males of Reproductive Potential: RECORLEV may lower testosterone levels and impair male and female fertility. Ketoconazole tablets (containing equal parts levoketoconazole and dextroketoconazole in a racemic mixture) have been demonstrated to lower serum testosterone in humans.

Pediatric Use: The safety and effectiveness of RECORLEV in pediatric patients below the age of 18 have not been established.

Renal Impairment: There is no experience with RECORLEV in patients with renal impairment. The overall pharmacokinetics of racemic ketoconazole in patients with renal impairment were not significantly different when compared with healthy subjects.

Hepatic Impairment: The use of 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.

OVERDOSAGE

In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered.

RECORLEV (levoketoconazole) tablets

RECORLEV (levoketoconazole) tablets