Levoketoconazole (Monograph)

Brand name: Recorlev
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: 1-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
Molecular formula: C₂₆H₂₈Cl₂N₄O₄
CAS number: 142128-57-2

Medically reviewed by Drugs.com on Feb 1, 2023. Written by ASHP.

Introduction

Cortisol synthesis inhibitor; a 2S,4R enantiomer of ketoconazole.

Uses for Levoketoconazole

Cushing’s Syndrome

Treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome who are not candidates for surgery or in whom surgery was not curative; designated an orphan drug by FDA for this use.

Safety and effectiveness of levoketoconazole for treatment of fungal infections not established; the drug is not approved for this use.

The treatment of choice for patients with Cushing's syndrome is usually surgery; medical therapies such as steroidogenesis inhibitors (e.g., levoketoconazole) are generally considered second-line therapies when surgery is not possible or ineffective.

Levoketoconazole Dosage and Administration

General

Pretreatment Screening

• Evaluate liver function tests (ALT, AST, and bilirubin concentrations) prior to treatment. Carefully consider the risks and potential benefits of initiating levoketoconazole in patients with AST or ALT above normal but ≤3 times the ULN.

• Perform ECG at baseline.

• Assess serum electrolyte concentrations, including potassium and magnesium; correct hypokalemia and hypomagnesemia prior to starting levoketoconazole.

Patient Monitoring

• Monitor liver enzymes and bilirubin weekly for at least 6 weeks following initiation of therapy, every 2 weeks for the next 6 weeks, monthly for the next 3 months, and then as clinically indicated. If therapy is interrupted or dosage is increased, monitor liver function tests weekly until a stable dosage is achieved.

• Perform ECG prior to each dose increase. After a stable dosage is achieved, monitor ECG routinely.

• Monitor potassium and magnesium concentrations periodically during therapy.

• Monitor 24-hour urinary free cortisol, morning serum or plasma cortisol, and patient's signs and symptoms of hypocortisolism periodically during therapy. During dosage titration, monitor cortisol levels from at least two 24-hour urinary free cortisol collections every 2–3 weeks until an adequate clinical response is reached. When maintenance dosage is achieved, monitor cortisol levels from at least two 24-hour urinary free cortisol collections at least every 1–2 months or as clinically indicated. If the 24-hour urine free cortisol levels remain above the upper normal limit after treatment with the maximum recommended dosage of 1200 mg daily, or the patient cannot tolerate treatment with levoketoconazole, consider discontinuing the drug and switching the patient to another therapy.

Administration

Oral Administration

Administer orally twice daily without regard to meals.

If a dose of levoketoconazole is missed, skip the missed dose and take the next dose at the next scheduled time; do not take an additional dose to replace the missed dose.

Dosage

Adults

Cushing’s Syndrome

Oral

Initially, 150 mg twice daily. May increase dosage by 150 mg daily every 2–3 weeks based on patient response (e.g., concentrations of urinary free cortisol) and tolerance until adequate response is achieved or a maximum dosage of 600 mg twice daily is reached. If 600 mg twice daily is not tolerated or if urinary free cortisol levels remain above the ULN after treatment with the maximum recommended dosage, consider discontinuing the drug.

Dosage Modification for Toxicity

If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, dosage may be reduced to 150 mg once daily.

Dosage Modification for Hepatotoxicity

If ALT or AST concentration ≥5 times the ULN with any total bilirubin concentrations or ALT or AST concentration ≥3 times the ULN with total bilirubin concentrations >2 times the ULN, permanently discontinue levoketoconazole.

If ALT or AST concentration ≥3 to <5 times the ULN with total bilirubin concentration ≤2 times the ULN, temporarily interrupt therapy; monitor liver function tests every 3 days until levels stabilize and then at least every 7–10 days until liver function returns to baseline. When liver function tests normalize and possible alternative etiologies have been addressed, therapy may be resumed at a reduced dosage; monitor liver function weekly for 1 month and then routinely thereafter before considering further dosage increases. If liver function test abnormalities significantly above baseline recur, permanently discontinue levoketoconazole.

If ALT or AST concentration >ULN but <3 times the ULN with any total bilirubin concentration or if liver function tests increase above baseline, consider interrupting therapy; monitor liver function tests at least every 7–10 days until values return to baseline. When liver function tests improve to baseline and possible alternative etiologies have been addressed, therapy may be resumed at a reduced dosage and titrated more slowly; monitor liver function tests weekly for 1 month to ensure that levels are stabilized before considering further dosage increases.

Dosage Modification for QT Prolongation

If QT interval (corrected for heart rate using Fridericia’s formula [QT_cF]) >500 msec, temporarily interrupt therapy and address possible contributing factors (e.g., hypokalemia, hypomagnesemia, concomitant therapy). When QT_cF interval returns to ≤500 msec, therapy may be resumed at a reduced dosage. If QT interval prolongation recurs, permanently discontinue levoketoconazole.

Dosage Modification for Hypocortisolism

If urine free cortisol or morning serum or plasma cortisol levels decrease to below target range or decrease rapidly, or if signs and/or symptoms of hypocortisolism occur, temporarily interrupt levoketoconazole therapy or reduce dosage.

If morning serum or plasma cortisol levels decrease to below target range and signs and/or symptoms of adrenal insufficiency or hypocortisolism occur, withhold levoketoconazole therapy and administer exogenous glucocorticoid replacement therapy. When cortisol levels improve to within target ranges and signs and/or symptoms of hypocortisolism have resolved, resume therapy at a reduced dosage. If the reduced dosage is well tolerated, but does not achieve an adequate clinical response, dosage may be titrated to the previous dosage associated with hypocortisolism.

Prescribing Limits

Adults

Cushing’s Syndrome

Oral

Maximum recommended dosage is 600 mg twice daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations. Not studied.

Contraindicated in patients with acute or poorly controlled chronic liver disease. (See Contraindications under Cautions.)

Renal Impairment

No specific dosage recommendations. Not studied.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

dexamethasone, Decadron, cyproheptadine, mifepristone

Cautions for Levoketoconazole

Contraindications

• Acute liver disease or poorly controlled chronic liver disease, including cirrhosis, baseline elevations of AST or ALT >3 times the ULN, recurrent symptomatic cholelithiasis, or extensive metastatic liver disease.

• History of drug-induced liver injury due to ketoconazole or any azole antifungal therapy requiring discontinuation of therapy.

• Concomitant use with drugs that cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes.

• Prolonged QT_cF interval (>470 msec) at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history).

• Concomitant use with certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-glycoprotein (P-gp).

• Known hypersensitivity to levoketoconazole, ketoconazole, or any ingredients in the formulation.

Warnings/Precautions

Warnings

Hepatotoxicity

Serious hepatotoxicity (sometimes fatal or requiring liver transplantation) reported in patients receiving ketoconazole, including patients with no obvious risk factors for liver disease. (See Boxed Warning.) Drug-induced liver injury (AST/ALT >3 times the ULN) reported in patients receiving levoketoconazole.

Contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT >3 times ULN, 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 with hepatotoxic drugs or excessive alcohol consumption.

Assess hepatic function tests prior to initiating levoketoconazole, regularly during therapy (more frequently during dosage titration), and as clinically indicated. If abnormal hepatic function tests occur, repeat tests within approximately 3 days following the initial abnormal hepatic test until test results are stable. Monitor hepatic function at least every 7–10 days thereafter until liver test abnormality resolves (or returns to baseline) or until alternative cause identified.

If AST or ALT concentrations <3 times the ULN or AST or ALT elevations ≥3 to <5 times the ULN and total bilirubin concentrations <2 times the ULN occur, interrupt therapy and monitor hepatic function; dosage reduction or permanent discontinuation of therapy may be necessary. If AST or ALT concentrations ≥5 times the ULN, or if AST or ALT concentrations ≥3 times the ULN and total bilirubin concentration >2 times the ULN occur, permanently discontinue levoketoconazole.

QT Interval Prolongation

Dose-dependent QT interval prolongation reported; may cause potentially life-threatening ventricular arrhythmias such as torsades de pointes. (See Boxed Warning.) QT interval prolongation generally resolves following interruption of therapy and correction of electrolyte abnormalities.

Perform ECGs to obtain a baseline QT_cF interval measurement and repeat regularly thereafter. Interrupt therapy if QT_c interval >500 msec; consider reinitiating at a decreased dosage when QT_c <500 msec and contributing factors are corrected. If QT interval prolongation recurs, permanently discontinue drug.

Correct hypokalemia and/or hypomagnesemia prior to initiating levoketoconazole, and periodically monitor potassium and magnesium concentrations during treatment; correct abnormalities as clinically indicated.

Contraindicated in patients with prolonged QT_c interval >470 msec at baseline or history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Caution advised in patients with other risk factors for QT interval prolongation (e.g., CHF, bradyarrhythmias, uncorrected electrolyte abnormalities); consider more frequent ECG monitoring in such patients.

Concomitant use with certain drugs known to prolong the QT interval associated with ventricular arrhythmias is contraindicated.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions reported in 1% of patients receiving levoketoconazole in clinical trials. Anaphylactic reactions and urticaria reported in patients receiving oral ketoconazole.

Other Warnings and Precautions

Hypocortisolism

Risk of hypocortisolism and potentially life-threatening adrenal insufficiency. Manifestations may include nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.

Hypocortisolism can occur at any time during treatment. Evaluate patients for precipitating causes of hypocortisolism (e.g., infection, physical stress). Periodically monitor 24-hour urine free cortisol (UFC), serum or plasma cortisol, and signs/symptoms of hypocortisolism.

Reduce dosage or interrupt levoketoconazole therapy if UFC levels or morning blood cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or signs/symptoms of hypocortisolism occur.

If serum or plasma cortisol levels are below target range and symptoms of adrenal insufficiency are present, discontinue levoketoconazole and initiate exogenous glucocorticoid replacement therapy. May restart drug at reduced dosage when UFC and serum or plasma cortisol levels are within target range, and/or signs/symptoms have resolved. Cortisol suppression may persist more than 4–6 hours after levoketoconazole is discontinued.

Risks Related to Decreased Testosterone

Reduced serum testosterone reported in men and women. Symptoms of reduced testosterone in men may include gynecomastia, impotence, and oligospermia; symptoms of reduced testosterone in women may include decreased libido and mood changes.

Specific Populations

Pregnancy

May cause fetal harm. Embryofetal toxicity (e.g., increased resorptions, fetal malformations, fetal death) observed in animals receiving oral racemic ketoconazole. Adequate data not available regarding use of levoketoconazole in pregnant women.

Pregnant women with untreated Cushing’s syndrome are at risk for maternal and fetal morbidity and mortality (e.g., gestational diabetes, gestational hypertension, pre-eclampsia, maternal death, miscarriage, intrauterine fetal demise, preterm birth, neonatal death). If levoketoconazole is used during pregnancy, consider whether potential benefits justify possible risks to the fetus.

Lactation

Not known whether levoketoconazole is distributed into human milk. Ketoconazole distributes into human milk. Because of potential for serious adverse reactions (e.g., liver toxicity) in nursing infants, breast-feeding not recommended during treatment and for 1 day after the final dose.

Females and Males of Reproduction Potential

May decrease testosterone levels and impair male and female fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Insufficient data to determine whether patients ≥65 years of age respond differently than younger adults.

Hepatic Impairment

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.

Not studied in patients with hepatic impairment. Clearance may be decreased based on extensive hepatic metabolism of racemic ketoconazole.

Renal Impairment

Not studied in patients with renal impairment. Pharmacokinetics of racemic ketoconazole not significantly different in patients with renal impairment compared with healthy subjects.

Common Adverse Effects

Adverse effects (≥20%): Nausea, vomiting, hypokalemia, hemorrhage/contusion, hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, peripheral edema.

Drug Interactions

Strong inhibitor of CYP3A4. Also inhibits CYP2B6 and CYP2C8 and induces CYP1A2. Does not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP2D6, and does not induce CYP2B6.

Inhibits P-glycoprotein (P-gp), organic cation transporter (OCT)2, and multidrug and toxin extrusion proteins (MATE)1, but does not inhibit organic anion transporting polypeptide (OATP)1B3, organic anion transporters (OAT)1 and OAT3, or MATE2K.

Drugs Affected by Hepatic Microsomal Enzymes and/or Efflux Transport Systems

CYP3A4 substrates or combined CYP3A4 and P-gp substrates: Increased plasma concentrations of the substrate drug, and increased risk of toxicity. Concomitant use with sensitive CYP3A4 substrates or combined CYP3A4 and P-gp substrates (e.g., alfentanil, avanafil, buspirone, conivaptan, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, vardenafil) contraindicated or not recommended.

CYP3A4 substrates or combined CYP3A4 and P-gp substrates that may increase QT interval: Concomitant use may increase the risk of QT interval prolongation and ventricular arrhythmias including torsades de pointes. Concomitant use with these drugs (e.g., bosutinib, cisapride, clarithromycin, cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat [in poor or intermediate metabolizers of CYP2D6 or those taking strong or moderate CYP2D6 inhibitors], ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, ranolazine) contraindicated.

P-gp, OCT2, or MATE1 substrates: Increased plasma concentrations and systemic exposure to the substrate drug, and increased risk of adverse reactions.

CYP2B6 and CYP2C8 substrates: Possible increased risk of adverse reactions of the substrate drug.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Increased systemic exposure to levoketoconazole and increased risk of adverse reactions. Concomitant use with strong inhibitors of CYP3A4, including certain antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) and glucocorticoid and progesterone receptor antagonists (e.g., mifepristone) not recommended. Discontinue strong CYP3A4 inhibitor 2 weeks before initiating levoketoconazole.

Strong CYP3A4 inducers: Decreased systemic exposure to levoketoconazole and reduced levoketoconazole efficacy. Concomitant use with strong inducers of CYP3A4 (e.g., isoniazid, rifabutin, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine, mitotane) not recommended. Discontinue strong CYP3A4 inducer 2 weeks before initiating levoketoconazole.

Specific Drugs

Levoketoconazole Pharmacokinetics

Absorption

Bioavailability

Increases in levoketoconazole peak plasma concentrations approximately dose-proportional and increases in AUC greater than dose-proportional over dose range of 150–600 mg.

Peak plasma concentrations of levoketoconazole achieved in approximately 1.5–2 hours.

Accumulation occurs following multiple doses of the drug.

Food

Administration of a single 600-mg dose with a high-fat meal increases AUC by 30% but does not alter peak plasma concentrations, and delays time to peak plasma concentrations by 2–4 hours; effects not considered clinically important.

Distribution

Extent

Not known if distributed into human milk.

Plasma Protein Binding

99.3%.

Elimination

Metabolism

Levoketoconazole: Metabolism studies not performed.

Racemic ketoconazole: Metabolized in the liver to several inactive metabolites (with respect to antifungal activity) by oxidation and degradation of the imidazole and piperazine rings; in addition, oxidative O-dealkylation and aromatic hydroxylation occurs. CYP3A4 is major enzyme involved in metabolism.

Elimination Route

Levoketoconazole: Elimination studies not performed.

Racemic ketoconazole: Eliminated principally in feces (57%) and urine (13%; 2–4% as unchanged drug).

Half-life

3–4.5 hours.

Special Populations

Population pharmacokinetic modeling suggests that pharmacokinetics of levoketoconazole not substantially affected by age or sex. However, the pharmacokinetics of levoketoconazole have not been formally studied in geriatric patients and in patients <18 years of age. Not known whether there are any differences in pharmacokinetics among race/ethnicity groups.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Cortisol synthesis inhibitor; the 2S,4R enantiomer of ketoconazole.

• Inhibits key enzymes in the synthesis of cortisol and testosterone, including CYP11B1 (11β hydroxylase), CYP11A1 (a cholesterol side-chain cleavage enzyme, which is the first step in the conversion of cholesterol to pregnenolone), and CYP17A1 (17α-hydroxylase).

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).

• Instruct patients on the importance of laboratory monitoring and adherence to their return-visit schedule.

• Inform patients that levoketoconazole may cause liver injury. Advise patients of the signs and symptoms of hepatotoxicity (e.g., right upper quadrant pain associated with nausea, unusual fatigue, signs of jaundice, unusual bruising or bleeding). Advise patients to contact their healthcare provider immediately if signs or symptoms of hepatotoxicity occur. Advise patients that liver tests will be measured before treatment and periodically thereafter.

• Advise patients to avoid excessive alcohol use while taking levoketoconazole.

• Inform patients that levoketoconazole may cause QT interval prolongation. Advise patients to contact their healthcare provider immediately if signs or symptoms of QT interval prolongation, which include severe lightheadedness (pre-syncope) or fainting (syncope), occur. Advise patients that an ECG will be taken before treatment and periodically thereafter. Advise patients that potassium and magnesium disturbances may require correction to aid in preventing QT interval prolongation.

• Inform patients that levoketoconazole may cause hypocortisolism. Advise patients of the signs and symptoms of hypocortisolism. Advise patients to report signs and symptoms of hypocortisolism to their healthcare provider promptly. Advise patients that cortisol in the blood or urine will be measured before treatment and periodically thereafter.

• Inform patients that levoketoconazole may cause hypersensitivity reactions. Advise patients to contact their healthcare provider if signs or symptoms of hypersensitivity reaction occur.

• Advise pregnant patients and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

• Advise patients not to breast-feed during treatment with levoketoconazole and for one day after the final dose.

• Advise patients of reproductive potential that levoketoconazole may impair fertility.

• Inform patients that levoketoconazole may interact with many drugs. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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