levoketoconazole

Contraindicated in:

Hypersensitivity to levoketoconazole or ketoconazole;
Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT >3 times upper limit of normal (ULN), history of drug-induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease;
Recurrent symptomatic cholelithiasis;
Concurrent use of QT interval prolonging drugs;
History of torsades de pointes, ventricular tachycardia, ventricular fibrillation, long QT syndrome, or QT interval prolongation at baseline;
Concurrent use of sensitive CYP3A4 substrates or dual CYP3A4 and P-glycoprotein substrates;
Lactation: Lactation.

Use Cautiously in:

HF, bradyarrhythmias, or uncorrected electrolyte abnormalities;
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension, peripheral edema, QT interval prolongation, syncope, TORSADES DE POINTES

Derm: dry skin, erythema, pruritus, rash, alopecia

Endo: adrenal insufficiency, gynecomastia, hypocortisolism

F and E: hypokalemia

GI: ↑liver enzymes, abdominal pain, diarrhea, dry mouth, dyspepsia, hepatotoxicity, nausea, vomiting

GU: uterine bleeding, ↓fertility, ↓libido, hypogonadism, impotence, urinary tract infection

Hemat: bleeding

Metab: ↓appetite

MS: arthritis, back pain, myalgia

Neuro: attention disturbance, depression, dizziness, fatigue, headache, insomnia, irritability

Resp: upper respiratory infection

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS)

Interactions ⬆ ⬇

Drug-drug:

May significantly ↑ levels and risk of torsades de pointes with bosutinib, clarithromycin, cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat, ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine; concurrent use contraindicated.
May ↑ levels and risk of toxicity of sensitive CYP3A4 substrates or dual CYP3A4 and P-glycoprotein substrates, including avanafil, buspirone, conivaptan, dabigatran, darifenacin, darunavir, digoxin, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, and vardenafil; concurrent use contraindicated.
May ↑ levels and risk of toxicity of metformin.
May ↑ levels and risk of rhabdomyolysis of atorvastatin; use lowest dose of atorvastatin.
Strong CYP3A4 inhibitors may ↑ levels and risk of toxicity; concurrent use not recommended. Avoid use of strong CYP3A4 inhibitors for 2 wk before and during treatment with levoketoconazole.
Strong CYP3A4 inducers may ↓ levels and effectiveness; concurrent use not recommended. Avoid use of strong CYP3A4 inducers for 2 wk before and during treatment with levoketoconazole.
↑risk of hepatotoxicity with other hepatotoxic agents, including alcohol; avoid concurrent use.
Drugs that ↑ gastric pH, including antacids, H2 antagonists, and proton pump inhibitors, ↓ absorption and effectiveness; delay administration of antacids for ≥2 hr after giving ketoconazole. Avoid concurrent use with H₂ antagonists or proton pump inhibitors.
Sucralfate↓ absorption and effectiveness; avoid concurrent use.

Availability ⬆ ⬇

Route/Dosage ⬆ ⬇

PO (Adults ): 150 mg twice daily; then ↑ dose by 150 mg/day every 2–3 wk based on urinary free cortisol levels and patient tolerability (max dose = 600 mg twice daily).

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Inhibits CYP11B1 (11β-hydroxylase), CYP11A1, and CYP17A1 ( (17α-hydroxylase), which inhibits synthesis of cortisol and testosterone.

Therapeutic effects:

Reduction in urinary free cortisol levels.

Classifications ⬆ ⬇

Therapeutic Classification: none assigned

Pharmacologic Classification: cortisol synthesis inhibitors

Pharmacokinetics ⬆ ⬇

Absorption: Well absorbed following oral administration.

Distribution: Widely distributed to tissues.

Protein Binding: 99.3%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme. Primarily excreted in feces (57%), with 13% excreted in urine (2–4% as unchanged drug).

Half-Life:

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1.5–2 hr	12 hr

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy.
Advise patient if dose is missed to take next dose at regularly scheduled time.
Instruct patient to notify health care professional immediately if signs and symptoms of liver injury (right upper abdominal pain, nausea, jaundice, dark urine, ↑ bruising or bleeding), QT interval prolongation (dizziness, fainting), or hypocortisolism (fatigue, weakness, ↓ appetite) occur.
Instruct patient to notify health care professional if hypersensitivity reaction, including urticaria, occurs.
Inform patient to notify health care professional if signs and symptoms of ↓ testosterone (gynecomastia, impotence, ↓ libido, mood changes) occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications.
Rep: Advise women of reproductive potential to notify health care professional of known or suspected pregnancy and not to breastfeed for 1 day after final dose. May impair fertility.

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Indications ⬇

Contraind./Precautions ⬆ ⬇