levoketoconazole (Rx)

Brand and Other Names:Recorlev
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 150mg

Cushing Syndrome

Indicated for treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative

Initial: 150 mg PO BID

Dose titration

  • Titrate by 150 mg daily, no more frequently than every 2-3 weeks based on 24-hr urine free cortisol levels and patient tolerability
  • Monitor cortisol levels from at least two 24-hr urine free cortisol collections every 2-3 weeks until an adequate clinical response achieved
  • Maximum recommended dosage: 600 mg BID
  • May reduce to 150 mg once daily if needed for reasons of tolerability

Dose monitoring for efficacy

  • Once maintenance dose achieved, monitor cortisol levels from at least two 24-hr urine free cortisol collections at least every 1-2 months or as indicated
  • If 24-hr urine free cortisol levels remain above ULN after treatment with maximum recommended dose (1200 mg/day) or patient cannot tolerate treatment, consider discontinuing and switching to another therapy

Dosage Modifications

Hepatoxicity

  • ALT/AST ≥5x ULN and any total bilirubin: Permanently discontinue
  • ALT/AST ≥3x ULN and total bilirubin >2x ULN: Permanently discontinue
  • ALT/AST ≥3 to <5x ULN and total bilirubin ≤2x ULN
    • Temporarily discontinue
    • Monitor liver tests q3days until levels are stable, and then at least q7-10 days until tests return to baseline levels
    • May restart at lower dosage and titrate more slowly once liver tests normalize and other possible contributing factors addressed
    • Before considering dosage increase, monitor liver tests weekly for 1 month and then routinely thereafter
    • Permanently discontinue if recurs after restarting
  • ALT/AST >ULN to <3x ULN and any total bilirubin
    • If liver tests increase above baseline, monitor liver tests at least q7-10 days until tests have returned to baseline levels; consider temporarily discontinuing levoketoconazole during this time
    • If discontinued, restart at lower dosage and titrate more slowly once liver tests return to baseline and other possible contributing factors addressed
    • Before considering dosage increase, monitor liver tests weekly for 1 month to ensure stability of liver tests

QT prolongation

  • Temporarily discontinue if QTcF interval >500 msec
  • After correcting other possible contributing factors (eg, hypokalemia, hypomagnesemia, use of concomitant drugs), may resume at lower dosage when QTcF interval returns to ≤500 msec
  • If QT interval prolongation recurs after restarting, permanently discontinue

Hypocortisolism

  • Decrease dose or temporarily discontinue if urine free cortisol or morning serum or plasma cortisol levels fall below target range, rapid decrease in cortisol levels, or if signs and/or symptoms consistent with hypocortisolism reported
  • Stop therapy 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
  • Reinitiate at lower dose when cortisol levels are within target ranges and signs and/or symptoms of hypocortisolism have resolved
  • May titrate to previous dose associated with hypocortisolism if reduced dose tolerated, but does not achieve an adequate clinical response

Hepatic impairment

  • Contraindicated with cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, 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

Renal impairment

  • Data are not available
  • Overall pharmacokinetics of racemic ketoconazole in patients with renal impairment were not significantly different when compared with healthy subjects

Dosing Considerations

Limitations of use: Not approved for the treatment of fungal infections; safety and effectiveness not established

Before initiation

  • Obtain baseline liver tests (ALT, AST, total bilirubin)
  • Carefully consider risks and potential benefits of initiating if AST or ALT above normal but ≤3x ULN
  • Obtain baseline ECG
  • Correct hypokalemia and hypomagnesemia

Safety monitoring

  • Hepatotoxicity
    • Serious hepatotoxicity reported, therefore frequent monitoring of liver tests recommended
    • Monitor AST, ALT, and bilirubin weekly for at least 6 weeks after starting, q2weeks for next 6 weeks, monthly for next 3 months, and then as clinically indicated
    • After any dose interruption or dose increase, monitor on weekly basis until stable dosage achieved
  • QT prolongation
    • Conduct an ECG before each dose increase; after stable dose established, monitor routinely for effect on the QT interval
    • Monitor blood potassium and magnesium levels periodically during treatment
  • Hypocortisolism
    • Monitor 24-hr urine free cortisol, morning serum or plasma cortisol, and signs and symptoms for hypocortisolism periodically during treatment

Safety and efficacy not established

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Adverse Effects

>10%

Erythema (43%)

Hemorrhage/contusion (23-40%)

Fatigue (18-39%)

Headache (21-38%)

Nausea/vomiting (30-37%)

Abdominal pain/dyspepsia (15-33%)

Hypokalemia (15-29%)

Arthritis (28%)

Upper respiratory infection (18-28%)

Myalgia (26%)

Hypertension (20-24%)

Abnormal uterine bleeding (20-24%)

Arrhythmia (19-24%)

Back pain (22%)

Insomnia/sleep disturbances (22%)

Peripheral edema (20%)

Diarrhea (15-19%)

Presyncope/syncope (18%)

Rash (17%)

UTI (6-16%)

Dizziness (15%)

Pruritus (15%)

QTcF change-from baseline >60 msec (14.7%)

Attention disturbance (14%)

Irritability (14%)

Decreased appetite (13%)

ALT/AST >3x ULN (13%)

Depression (12%)

Dry skin (11-12%)

Dry mouth (11%)

Alopecia (6-11%)

Hepatoxicity

  • AST/ALT >ULN (45%)
  • ≥1 liver related adverse reaction (27%)
  • Liver enzyme elevation (20%)
  • AST/ALT >3x ULN (11%)

1-10%

Adrenal insufficiency (3-10%)

Hypocortisolism (7%)

Gastrointestinal infection (5-6%)

Decreased libido (5%)

Hypogonadism (2-4%)

Gynecomastia (3%)

QTcF >500 msec (2.4%)

Hypersensitivity (1%)

Hepatoxicity

  • AST/ALT >5x ULN (5%)
  • AST/ALT >10x ULN (3%)
  • Hepatic pain (4%)
  • Drug-induced liver injury (2%)
  • Liver disorders (2%)
  • Hepatic steatosis (1%)

Postmarketing Reports

Following identified with ketoconazole

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 (eg, 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

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Warnings

Black Box Warnings

Hepatotoxicity

  • Serious hepatotoxicity cases reported, some with fatal outcome or requiring liver transplantation
  • Some patients had no obvious risk factors for liver disease
  • Contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, 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
  • Evaluate liver enzymes before and during treatment
  • Interrupt treatment immediately if signs of hepatotoxicity occur

QT prolongation

  • Associated with dose-related QT interval prolongation
  • QT interval prolongation may lead to life-threatening ventricular dysrhythmias (eg, torsades de pointes)
  • Contraindicated with other drugs that prolong QT interval associated with ventricular arrhythmias, including torsades de pointes, and use in patients with prolonged QTcF interval >470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history)
  • Perform ECG and correct hypokalemia and hypomagnesemia before and during treatment
  • Temporarily discontinue levoketoconazole if QTcF interval >500 msec

Contraindications

Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT >3x ULN, recurrent symptomatic cholelithiasis, 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

Coadministration with 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 long QT syndrome (including first-degree family history)

Known hypersensitivity to levoketoconazole, ketoconazole or any excipient in drug product

Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-glycoprotein (P-gp)

Cautions

Serious hepatotoxicity reported, including fatal outcomes or requiring liver transplantation with use of oral ketoconazole, racemic mixture from which levoketoconazole is derived; prompt recognition of liver injury essential; educate patients on symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur

Associated with dose-related QT interval prolongation (see contraindications, drug interactions, dosage modification, dosing considerations); use 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

Hypersensitivity reactions reported

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

Hypocortisolism

  • Levoketoconazole lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency
  • 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
  • Stop levoketoconazole 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 discontinuation, cortisol suppression may persist beyond the 4-6 hr half-life of levoketoconazole

Drug interaction overview

  • CYP3A4 substrate (major); strong CYP3A4 inhibitor
  • QT prolonging drugs
    • Contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes
  • CYP3A4 or CYP3A4/P-gp substrates that prolong QT
    • Contraindicated with CYP3A4 and/or P-gp substrates that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes
    • Levoketoconazole inhibits CYP3A4 and P-gp, which may increase substrate systemic exposure and risk for QT prolongation
  • Sensitive CYP3A4 or CYP3A4/P-gp substrates
    • Contraindicated or not recommended
    • Levoketoconazole inhibits CYP3A4 and P-gp, which may increase sensitive substrate systemic exposure
  • Atorvastatin
    • Reduce atorvastatin dose
    • Levoketoconazole increases plasma concentration of atorvastatin and may increase risk of atorvastatin-associated myopathy and rhabdomyolysis
    • Use lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dose >20 mg/day
  • Metformin and other OCT2 and MATE substrates
    • Monitor
    • Levoketoconazole increases metformin concentration and may increase risk of metformin’s adverse reactions; may increase plasma concentrations of other OCT2 and MATE substrates and increase risk of their adverse reactions
    • During levoketoconazole dosage titration, monitor blood glucose, kidney function, and vitamin B12 per metformin prescribing information and adjust metformin dosage as needed
  • Strong CYP3A4 inhibitors
    • Not recommended
    • May increase plasma concentration of levoketoconazole and increase risk of adverse effects
    • Avoid use of these drugs from 2 weeks before and during treatment
  • Strong CYP3A4 inducers
    • Not recommended
    • May decrease plasma concentration of levoketoconazole and decrease efficacy
    • Avoid use of these drugs from 2 weeks before and during treatment
  • Gastric acid neutralizers
    • Take gastric acid neutralizer (eg, aluminum hydroxide) at least 2 hr after levoketoconazole
    • Impairs levoketoconazole absorption
  • Gastric acid suppressors or sucralfate
    • Avoid
    • Gastric acid suppressors (eg, H2 antagonists, PPIs) and sucralfate impair levoketoconazole absorption
  • Alcohol
    • Avoid excessive consumption
    • Disulfiram-like reactions reported
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Pregnancy & Lactation

Pregnancy

Levoketoconazole is the 2S, 4R enantiomer of ketoconazole

Available published data from case series and case-control studies on use of racemic ketoconazole during pregnancy are insufficient to determine drug-associated risk of major birth defects

Data are unavailable regarding risk of miscarriage

Animal studies

  • No animal reproduction studies conducted with levoketoconazole
  • Levoketoconazole constituted about 70% of exposure in humans and animals after racemic ketoconazole administration
  • Embryotoxic effects observed in pregnant mice, rats, and rabbits, and fetal malformations observed in rats, following oral dosing of racemic ketoconazole during organogenesis at doses equal and less than the maximum recommended human dose (MRHD), respectively

Clinical considerations

  • Active Cushing syndrome during pregnancy associated with increased risk of maternal and fetal morbidity and mortality, including gestational diabetes, gestational hypertension, preeclampsia, maternal death, miscarriage, intrauterine fetal demise, preterm birth, and neonatal death
  • Labor or delivery
    • Dystocia (difficult labor) observed in mice and rats administered oral ketoconazole during organogenesis at exposures below the MRHD of levoketoconazole (BSA)
    • Clinical relevance of these findings for humans is unknown

Infertility

  • May lower testosterone and impair male and female fertility
  • Effect reversible upon discontinuation

Lactation

Data are unavailable regarding effects on milk production

Data from 1 lactating woman show ketoconazole present in human milk in low amounts, with no reported adverse effects on the breastfed infant; however, these limited data are insufficient to determine risk to breastfed infants with exposure to ketoconazole through breast milk

Advise patients not to breastfeed during treatment and for 1 day (5 half-lives) after final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Levoketoconazole is the purified 2S,4R enantiomer of ketoconazole

In vitro, levoketoconazole inhibits key steps in cortisol and testosterone synthesis, principally those mediated by CYP11B1 (11β hydroxylase), and CYP17A1 (17α-hydroxylase)

Inhibition of CYP11A1 blocks cleavage of the cholesterol side-chain, which is the first step in converting cholesterol to pregnenolone; also blocks conversion of 11-deoxycortisol to cortisol

Absorption

Peak plasma time: 1.5-2 hr (fasting); 4 hr (high-fat meal); not clinically significant

Distribution

Protein bound: 99.3%

Vd: 31-41 L

Metabolism

Substrate of intestinal (and liver) efflux transporter P-gp

No in vitro or in vivo studies of levoketoconazole metabolism performed

Racemic ketoconazole metabolized extensively in liver (mostly by CYP3A4) to several inactive metabolites (with respect to antifungal activity)

Major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings; oxidative O-dealkylation and aromatic hydroxylation also occurs

Elimination

Half-life: 3-4.5 hr (single dose); 4-6 hr (multiple doses)

Excretion: Urine (13% racemic ketoconazole [2-4% unchanged]); feces (57% racemic ketoconazole)

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Administration

Oral Administration

May take with or without food

Missed dose: Take next dose at regularly scheduled time

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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Images

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Patient Handout

A Patient Handout is not currently available for this monograph.
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Formulary

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Tier Description
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.