Levoketoconazole

Levoketoconazole is a prescription medication used for the treatment of endogenous hypercortisolemia in adults with Cushing syndrome for whom surgery is not an option or has not been curative.

• Levoketoconazole is available under the following different brand names: Recorlev

Common side effects of Levoketoconazole include:

• nausea/vomiting
• low blood potassium (hypokalemia)
• bleeding/bruising
• high blood pressure (hypertension) 
• headache
• liver injury 
• abnormal uterine bleeding 
• redness
• fatigue
• abdominal pain/indigestion 
• arthritis
• upper respiratory infection 
• muscle pain
• irregular heartbeat (arrhythmia)
• back pain
• insomnia/sleep disturbances 
• swelling of extremities
• dizziness
• diarrhea
• decreased appetite 
• dry mouth 
• dry skin
• adrenal insufficiency

Serious side effects of Levoketoconazole include:

• hives
• difficult breathing
• swelling of the face, lips, tongue, or throat
• fast or pounding heartbeats, fluttering in the chest, shortness of breath, and sudden dizziness (like you might pass out)
• liver problems--loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
• decreased adrenal gland hormones--nausea, vomiting, stomach pain, loss of appetite, feeling tired or light-headed, muscle or joint pain, skin discoloration, craving salty foods
• Men’s--breast enlargement and erectile dysfunction (impotence)
• Women’s--low desire for sex and mood changes
• low potassium level--leg cramps, constipation, irregular heartbeats, fluttering in the chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling
• severe lightheadedness

Rare side effects of Levoketoconazole include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 150 mg

Cushing syndrome

Adult dosage

• Initial: 150 mg orally two times a day
• Dose titration
  • Titrate by 150 mg daily, no more frequently than every 2-3 weeks based on 24-hours urine free cortisol levels and patient tolerability
  • Monitor cortisol levels from at least two 24-hour urine-free cortisol collections every 2-3 weeks until an adequate clinical response achieved
  • Maximum recommended dosage: 600 mg two times a day
• May reduce to 150 mg once daily if needed for reasons of tolerability
  • Dose monitoring for efficacy
  • Once the maintenance dose 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 ULN after treatment with the maximum recommended dose (1200 mg/day) or the patient cannot tolerate treatment, consider discontinuing and switching to another therapy

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Levoketoconazole has no noted severe interactions with any other drugs
• Levoketoconazole has no noted serious interactions with any other drugs
• Levoketoconazole has no noted moderate interactions with any other drugs
• Levoketoconazole has no noted minor interactions with any other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT of more than 3 × 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 of more than 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)

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Levoketoconazole?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Levoketoconazole?”

Cautions

• Serious hepatotoxicity reported, including fatal outcomes, or requiring liver transplantation with the use of oral ketoconazole, the 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; use 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
• 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 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 the target range and signs and/or symptoms of adrenal insufficiency, or hypocortisolism, are present
  • After discontinuation, cortisol suppression may persist beyond the 4-6 hours 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 the plasma concentration of atorvastatin and may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis
    • Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dose above 20 mg/day
    • Metformin and other OCT2 and MATE substrates
  • Monitor
    • Levoketoconazole increases metformin concentration and may increase the risk of metformin’s adverse reactions; may increase plasma concentrations of other OCT2 and MATE substrates and increase the 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 the plasma concentration of Levoketoconazole and increase the risk of adverse effects
    • Avoid the use of these drugs from 2 weeks before and during treatment
  • Strong CYP3A4 inducers
    • Not recommended
    • May decrease the plasma concentration of Levoketoconazole and decrease the efficacy
    • Avoid the use of these drugs from 2 weeks before and during treatment
  • Gastric acid neutralizers
    • Take gastric acid neutralizer (eg, aluminum hydroxide) at least 2 hours 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

Pregnancy and Lactation

• Levoketoconazole is the 2S, 4R enantiomer of ketoconazole
• Available published data from case series and case-control studies on the use of racemic ketoconazole during pregnancy are insufficient to determine a drug-associated risk of major birth defects
• Data are unavailable regarding the risk of miscarriage
• Clinical considerations
  • Active Cushing syndrome during pregnancy is associated with an 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) was 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 men's and women's fertility
  • Effect reversible upon discontinuation
• Lactation
  • Data are unavailable regarding the 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 the 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 the final dose