2.1 Laboratory Testing Prior to RECORLEV Initiation

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

2.2 Recommended Dosage, Titration, and Monitoring for Efficacy

• Initiate dosage at 150 mg orally twice daily, with or without food [see Clinical Pharmacology (12.3)].
• Titrate the dosage by 150 mg daily, no more frequently than every 2-3 weeks based on 24-hour urine free cortisol levels and patient tolerability [see Dosage and Administration (2.4)]. Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 2-3 weeks until an adequate clinical response is achieved.
• The maximum recommended dosage is 1200 mg per day, administered as 600 mg twice daily.
• The dosage may be reduced to 150 mg once daily if needed for reasons of tolerability [see Dosage and Administration (2.3, 2.4)].
• Once the maintenance dosage is achieved, monitor cortisol levels from at least two 24-hour urine free cortisol collections at least every 1-2 months or as indicated.
• If 24-hour urine free cortisol levels remain above the upper normal limit after treatment with the maximum recommended dosage of 1200 mg per day, or the patient cannot tolerate treatment with RECORLEV, consider discontinuing RECORLEV and switching patient to another therapy.

2.3 Monitoring for Safety

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

Hepatotoxicity

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

QT Prolongation

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

Hypocortisolism

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

2.4 Dosage Interruptions and Modifications

Hepatotoxicity

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

QT Prolongation

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

Hypocortisolism

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

2.5 Missed Dose

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

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 (4)].

Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV [see Drug Interactions (7.3)].

Prompt recognition of liver injury is essential. At baseline, obtain liver tests [see Dosage and Administration (2.1)]. During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration [see Dosage and Administration (2.3)].

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 (2.4)].

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

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 (7.1, 7.2)].

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 (4), Drug Interactions (7.1, 7.2)].

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 (2.1, 2.3)]. 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 (2.4)].

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 (6.1)]. 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 (2.3)].

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 (2.4)].

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 (2.4)]. 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.

5.4 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in 1% of patients treated with RECORLEV in the clinical trials [see Adverse Reactions (6.1)].

Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole [see Adverse Reactions (6.2)].

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

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of RECORLEV was evaluated in a multicenter, randomized-withdrawal study (Study 1) and in a multicenter, single-arm, open-label study (Study 2). During the two studies, 166 patients were exposed to RECORLEV, of which 104 patients were exposed for more than 6 months and 51 patients were exposed for at least 1 year. In both studies, most patients took RECORLEV twice daily in total daily dosages ranging from 300 mg to 1200 mg [see Clinical Studies (14)].

Adverse reactions, excluding hepatic injury, reported in ≥10% of patients treated with RECORLEV in Study 1 are presented in Table 2 listed in order of overall decreasing frequency of events.

Other notable adverse reactions which occurred with a frequency less than 10% during Study 1 were: alopecia (6%), gastrointestinal infection (6%), urinary tract infection (6%), hypogonadism (2%), and hypersensitivity (1%).

Adverse reactions, excluding hepatic injury, reported in ≥10% of patients treated with RECORLEV in Study 2 are presented in Table 3 listed in order of overall decreasing frequency of events.

Other notable adverse reactions which occurred with a frequency less than 10% during Study 2 were: gastrointestinal infections (5%), decreased libido (5%), hypogonadism (4%), adrenal insufficiency (3%), and gynecomastia (3%).

Description of Selected Adverse Reactions

Hepatic Injury and Elevated Liver Function Tests

Liver-related adverse reactions reported in patients treated with RECORLEV in Studies 1 and 2 are presented in Table 4. Table 5 summarizes patients who had at least one ALT or AST measurement greater than the upper limit of reference range (ULN) in post baseline visits in Studies 1 and 2 combined who had tests in the normal range at baseline. There were 11 out of 166 patients who had an AST or ALT above the ULN to ˂3 x ULN at baseline. Of these patients, 3 had increases above 3 x ULN, and none had increases above 5 x ULN. Liver test abnormalities improved with cessation of medication.

QTc Interval Prolongation

In Study 1 and 2, there were 4 (2.4%) patients who experienced QTcF>500 msec, and 23 (14.7%) patients who experienced change-from-baseline QTcF >60 msec, respectively [see Warnings and Precautions (5.2)]. Adverse reactions reported around the same time that may have been associated with QT prolongation included fatigue, hypertension, nausea/vomiting, and ventricular extrasystoles (seeTables 2 and 3).

Hypocortisolism

Hypocortisolism was reported in 11 (7%) of 166 patients across Studies 1 and 2, with events starting on median study day 96 (range 26-166). The majority of cases were managed by reducing the dosage or temporarily interrupting treatment with RECORLEV.

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

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 6 presents 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.

7.2 Effect of Other Drugs on RECORLEV

Table 7 presents clinically significant drug interactions that affect RECORLEV.

7.3 Alcohol

Patients should be advised against excessive alcohol consumption while using RECORLEV [see Warnings and Precautions (5.1)]. 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.

8.1 Pregnancy

Risk Summary

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 (see Clinical Considerations). 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 (see Data). Advise pregnant women of the potential risk to a fetus and consider whether the benefits of treatment with RECORLEV outweigh the risks.

The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15−20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

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).

Labor or Delivery

Dystocia (difficult labor) was noted in mice and rats administered oral ketoconazole during the period of organogenesis at exposures below the MRHD of levoketoconazole (by body surface area (BSA)). The clinical relevance of these findings for human is unknown.

Data

Animal Data

Racemic ketoconazole containing levoketoconazole was administered orally to rats, mice, and rabbits during the period of organogenesis. Levoketoconazole constituted about 70% of the exposure in animals after racemic ketoconazole administration.

Mice were administered 10, 20, and 40 mg/kg/day ketoconazole during the period of organogenesis (gestation days 6 to 18). Embryolethality (resorptions and still births) was observed at ≥ 20 mg/kg/day (below the MRHD of levoketoconazole based on BSA comparison). There was no maternal toxicity in mice up to the highest dose of 40 mg/kg/day (below the MRHD of levoketoconazole by BSA), however, females failed to deliver naturally and Cesarean examination 3 days after the due date showed increased resorptions and dead fetuses.

Rats were administered 10, 20, 40, and 80 mg/kg/day during the period of organogenesis (gestation days 6 to 18). Increased incidences of resorbed fetuses and still births were noted at ≥40 mg/kg/day (below the MRHD of levoketoconazole by BSA). Fetal malformations (oligodactyly, syndactyly, absence of metacarpal and/or metatarsal bones, and cleft palate) were noted at ≥80 mg/kg/day of ketoconazole (at the MRHD of levoketoconazole by BSA). Dystocia and prolonged gestation were observed in rats at ≥10 mg/kg/day (below the MRHD of levoketoconazole by BSA).

In rabbits, oral gavage doses of 0, 10 and 40 mg/kg/day ketoconazole were administered during the period of organogenesis (gestation days 6 through 18). Increased incidences of resorbed fetuses and still births were observed at ≥10 mg/kg/day (below MRHD of levoketoconazole by BSA).

8.2 Lactation

Risk Summary

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.

8.3 Females and Males of Reproductive Potential

Infertility

RECORLEV may lower testosterone levels [see Warnings and Precautions (5.5)] 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. Once therapy with ketoconazole tablets was discontinued, serum testosterone levels returned to baseline values. Testosterone levels are impaired with ketoconazole doses of 800 mg per day and abolished by 1600 mg per day. Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia. In rat fertility studies, oral ketoconazole administered at doses equivalent to the MRHD of levoketoconazole by BSA during premating to implantation caused impaired fertility in male and female rats. In dog fertility studies, levoketoconazole targeted the reproductive tissues of male dogs in a dose-dependent manner with associated effects on spermatogenesis and maturation of spermatozoa. The effect was reversible upon discontinuation of treatment [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 166 patients in clinical trials with RECORLEV, 12 (7%) were 65 years and older, with one patient 75 years of age. Clinical studies of RECORLEV did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 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.

8.7 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 [see Contraindications (4), Warnings and Precautions (5.1)].

12.1 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).

12.2 Pharmacodynamics

Cardiac Electrophysiology

The largest mean increase in QTc was 24 msec (UCI: 31 msec) following administration of levoketoconazole 150 mg to 600 mg twice daily (the approved recommended dosage) in patients with endogenous Cushing’s syndrome. The increase in QTc was dose-related.

12.3 Pharmacokinetics

Absorption

Peak plasma concentrations of levoketoconazole occur approximately 1.5 to 2 hours following oral administration of a single dose of RECORLEV under fasted conditions regardless of dose. In healthy volunteers, Cmax increases approximately proportionally with dose, while AUC increases greater than dose proportionally from 150 mg to 600 mg. Levoketoconazole accumulates in plasma during multiple dosing of RECORLEV.

Levoketoconazole is a substrate of the intestinal (and liver) efflux transporter, P-gp.

Effect of Food

In a healthy volunteer study (N = 24), subjects administered a single, 600 mg oral dose of RECORLEV tablets with a high-fat meal (total caloric content of 875 calories; 160 protein calories, 170 carbohydrate calories, and 545 fat calories) resulted in an increase of AUC by 30% and no change in Cmax. The median Tmax was delayed from 2 to 4 hours. These changes are not considered to be clinically significant.

Distribution

Levoketoconazole has an apparent volume of distribution of 31 to 41 L, approximating total body water. Protein binding of levoketoconazole in human plasma is high (99.3%).

Elimination

Metabolism

No in vitro or in vivo studies of levoketoconazole metabolism have been performed. Racemic ketoconazole is metabolized extensively in the liver to several inactive metabolites (with respect to antifungal activity). CYP3A4 is the major enzyme involved in the metabolism of ketoconazole. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings. In addition, oxidative O-dealkylation and aromatic hydroxylation occurs.

Excretion

Levoketoconazole is eliminated from plasma with a half-life of 3 to 4.5 hours after a single dose and 4 to 6 hours after multiple doses.

A mass-balance study has not been performed with levoketoconazole. Approximately 13% of a racemic ketoconazole dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract with about 57% being excreted in the feces.

Specific Populations

Population pharmacokinetic modeling data from patients with Cushing’s syndrome suggest there is no impact of age or sex on the pharmacokinetics of levoketoconazole. The pharmacokinetics of levoketoconazole have not been formally studied in geriatric patients. Levoketoconazole has not been studied in patients younger than 18 years of age. Differences in pharmacokinetics among race/ethnicity groups are unknown.

Patients with Renal or Hepatic Impairment

Levoketoconazole has not been studied in patients with renal or hepatic impairment. The overall pharmacokinetics of racemic ketoconazole was not significantly altered in patients with renal failure when compared with healthy volunteers. [see Contraindications (4)]. Given the extensive hepatic metabolism of ketoconazole, it is expected that clearance would be reduced in patients with impaired liver function.

Drug Interaction Studies

Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. Concomitant administration of medications that are substrates of these enzymes or transporters may have their plasma concentrations affected by RECORLEV [see Drug Interactions (7.1)].

Clinical drug interaction studies were conducted to evaluate the effects of levoketoconazole on the pharmacokinetics of atorvastatin, felodipine, and metformin in healthy volunteers. Results are displayed in Table 8. For clinical recommendations regarding these interactions, [see Drug Interactions (7.1)].

In Vitro Studies Where Drug Interaction Potential was not Further Evaluated Clinically

In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8, and induces CYP1A2.

Levoketoconazole does not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP2D6, does not induce CYP2B6, and does not inhibit the OATP1B3, OAT1, OAT3, or MATE2-K transporters.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Levoketoconazole has not been evaluated for carcinogenic effects. Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a 24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80 mg/kg/day of ketoconazole. The high dose in these studies was less than the MRHD of levoketoconazole in the mouse and equal to the MRHD of levoketoconazole in rats based on a BSA comparison.

Mutagenesis

Mutagenic potential of levoketoconazole has not been evaluated. Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay.

Impairment of Fertility

In animal fertility studies, oral ketoconazole impaired both male and female fertility in rats in a dose and duration dependent manner. In female rats, oral doses up to 40 mg/kg of ketoconazole (lower than the MRHD for levoketoconazole by BSA) had no effect on fertility. Doses of ≥75 mg/kg of ketoconazole (at the MRHD for levoketoconazole by BSA) decreased the pregnancy rate and number of implantation sites, and in males decreased sperm content (motility, count, morphology), which correlated with lower plasma testosterone levels and testicular histological changes. When administered for longer durations (up to 3 months), decreased fertility in male rats was observed at doses as low as 24 mg/kg/day of ketoconazole (lower than the MRHD for levoketoconazole by BSA).

In male beagle dogs, an oral dose of 25 mg/kg/day ketoconazole for up to 4 weeks (at the MRHD for levoketoconazole by BSA) resulted in decreased sperm motility, decreased sperm count, increased abnormal sperm and atrophy of the testes. These effects were reversed after withdrawal of treatment.