Generic Name

Levoketoconazole

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Classification

FDA Approved Indications

• Treatment of Cushing's syndrome in adult patients

Mechanism of Action

Levoketoconazole inhibits fungal cytochrome P450 enzymes, particularly 14α-demethylase, disrupting ergosterol synthesis, which is vital for fungal cell membrane integrity. It also inhibits adrenal steroidogenesis by blocking cortisol synthesis enzymes, thereby reducing cortisol levels in patients with Cushing's syndrome.

Dosage and Administration

Adult: The recommended starting dose is 600 mg twice daily, titrated based on response and tolerability. The dosing regimen may be adjusted according to the patient's clinical response and adverse effects.

Pediatric: Not approved for pediatric use.

Geriatric: Dose adjustments may be necessary due to increased sensitivity and comorbidities; start at lower doses and titrate carefully.

Renal Impairment: No specific dose adjustment recommended; monitor closely.

Hepatic Impairment: Use with caution; hepatic function monitoring is advised, and dose adjustments may be necessary depending on severity.

Pharmacokinetics

Absorption: Bioavailability increases with food; consistent administration with regard to meals is recommended.

Distribution: Widely distributed; highly protein-bound (~99%).

Metabolism: Primarily metabolized in the liver via CYP3A4 and CYP2C9 enzymes.

Excretion: Excreted mainly via feces; minimal urinary excretion.

Half Life: Approximately 4-6 hours; long half-life of active metabolites may extend effects.

Contraindications

• Hypersensitivity to levoketoconazole or other azole antifungals.
• Use with caution in patients with hepatic impairment.

Precautions

• Monitor liver function regularly. Avoid concomitant use with drugs that are highly dependent on CYP3A4 for clearance and have a narrow therapeutic index. Be aware of potential drug interactions and adverse effects. Use with caution during pregnancy and lactation; consult specific guidelines and weigh risks versus benefits.

Adverse Reactions - Common

• Nausea (Common)
• Headache (Common)
• Hepatotoxicity (elevated liver enzymes) (Uncommon)

Adverse Reactions - Serious

• Hepatotoxicity leading to liver failure (Rare)
• QT prolongation (Rare)
• Allergic reactions, including rash, anaphylaxis (Rare)

Drug-Drug Interactions

• CYP3A4 inducers (e.g., rifampin) may decrease effectiveness.
• CYP3A4 inhibitors (e.g., ketoconazole) may increase levoketoconazole levels.
• Caution with drugs affecting QT interval.

Drug-Food Interactions

• Food increases absorption; consistent administration with meals recommended.

Drug-Herb Interactions

• Potential increased risk of liver toxicity with herbal products like kava or green tea extract.

Nursing Implications

Patient/Family Teaching

• Take medication with food to enhance absorption.
• Report signs of liver problems: yellowing of skin or eyes, dark urine, severe fatigue.
• Avoid concurrent use of other QT-prolonging drugs.
• Limit alcohol intake to reduce liver strain.
• Attend all scheduled lab assessments.

Special Considerations

Black Box Warnings:

• Hepatotoxicity—potential for serious liver injury; monitor liver function tests regularly.

Genetic Factors: Variability in CYP3A4 metabolism may affect drug levels.

Lab Test Interference: May alter results of some hepatic function tests.

Overdose Management

Signs/Symptoms: Nausea, vomiting, dizziness, hepatotoxicity signs, arrhythmias.

Treatment: Supportive care. No specific antidote available. Consider gastric lavage or activated charcoal if ingestion was recent. Monitor liver function and cardiac status closely.

Storage and Handling

Storage: Store at room temperature, away from light and moisture.

Stability: Stable under recommended storage conditions for the duration of shelf life.