Levoketoconazole - Indications, Contraindications, Dosage, Warning, and Precautions

Overview:

Levoketoconazole is a selective cortisol synthesis inhibitor, meaning it targets the enzymes involved in the production of cortisol. By doing so, it helps to lower the levels of cortisol in the body, addressing the underlying cause of Cushing's syndrome. The medication underwent clinical trials to assess its safety and efficacy in reducing cortisol levels. Positive trial results led to submitting a New Drug Application (NDA) to the United State Food and Drug Administration (FDA). In December 2020, the FDA approved Levoketoconazole for treating endogenous Cushing's syndrome in adults. Levoketoconazole's approval provided a significant advancement in the management of Cushing's syndrome, offering an alternative therapeutic option, particularly for those who may not be suitable candidates for surgery or have not responded well to other treatments.

Drug Group:

Levoketoconazole belongs to the drug class known as cortisol synthesis inhibitors. Specifically, it is a selective inhibitor of 11-beta-hydroxylase, an enzyme crucial in the production of cortisol. This drug class addresses conditions associated with excess cortisol production, such as Cushing's syndrome, by targeting the enzymes responsible for cortisol synthesis in the adrenal glands.

Available Doses and Dosage Forms:

• Dosage: The treatment begins with an oral dosage of 150 mg (milligrams) twice daily.

• Titration: Titrate the dosage by 150 mg daily. Adjust the dosage at most every two to three weeks.

• Maximum Recommended Dosage: The maximum recommended dosage is 1200 mg daily.

For Patients:

What Is Cushing's Syndrome?

Cushing's syndrome is a medical condition characterized by excessive and extended exposure to elevated cortisol levels, a hormone produced by the adrenal glands. This disorder can result from various causes, the most common being the overuse or prolonged administration of corticosteroid medications. Additionally, tumors in the pituitary gland, adrenal glands, or elsewhere in the body can lead to an abnormal increase in cortisol production.

The symptoms of Cushing's syndrome are diverse. They can include weight gain, particularly in the abdominal area, a rounded face (a moon face), skin thinning, easy bruising, muscle weakness, and fatigue. Individuals with Cushing's syndrome may also experience shifts in mood, including heightened irritability or feelings of depression, as well as irregular menstrual cycles in women.

Effective management of Cushing's syndrome often requires a multidisciplinary approach involving endocrinologists, neurosurgeons, and other healthcare professionals. Timely identification and proper treatment are essential for mitigating symptoms, preventing complications, and improving the overall quality of life for individuals affected by this disorder.

How Does Levoketoconazole Work?

Levoketoconazole operates by selectively inhibiting the enzyme 11-beta-hydroxylase, a key player in cortisol synthesis. By impeding this enzyme, the medication disrupts the production of cortisol, the hormone associated with conditions like Cushing's syndrome. This targeted action helps regulate cortisol levels, addressing the disorder's underlying cause and alleviating associated symptoms. Levoketoconazole's mechanism offers a more specific and effective approach than its predecessor, Ketoconazole, with the potential to provide improved therapeutic outcomes for individuals with cortisol-related disorders.

What Is the Dosage of Levoketoconazole?

The typical starting dosage of Levoketoconazole is 150 mg (milligrams) orally twice daily, with potential adjustments based on individual response and tolerability.

How Effective Is Levoketoconazole?

Levoketoconazole is a medication primarily used for the treatment of Cushing's syndrome, a disorder characterized by excessive cortisol production. Its effectiveness in managing Cushing's syndrome has been demonstrated in clinical studies, where it has shown promise in reducing cortisol levels and improving associated symptoms. As with any medication, individual responses can vary, and effectiveness may depend on factors such as the underlying condition, patient characteristics, and adherence to the prescribed treatment plan. Levoketoconazole's efficacy is typically assessed based on its ability to normalize cortisol levels and alleviate Cushing's syndrome symptoms.

What Are the Things to Inform the Doctor Before Taking Levoketoconazole?

The things to inform the doctor before taking Levoketoconazole are as follows:

• Notify the healthcare provider and pharmacist of any allergies the patient may have to Levoketoconazole, Ketoconazole, other medications, or ingredients in Levoketoconazole tablets.

• Request a comprehensive list of ingredients from the pharmacist.

• Disclose the use of medications such as Avanafil, Buspirone, Conivaptan, Dabigatran, Darifenacin, Darunavir, Digoxin, Everolimus, Fexofenadine, Ibrutinib, Lomitapide, Lovastatin, Midazolam, Naloxegol, Nisoldipine, Saquinavir, Simvastatin, Sirolimus, Tacrolimus, Tipranavir, Triazolam, and Vardenafil.

• Share details about other prescription or nonprescription medications, vitamins, supplements, and herbal products.

• The healthcare provider may need to adjust medication doses or monitor closely for side effects due to potential interactions.

• If the patient takes antacids, administer them two hours after Levoketoconazole.

• Inform the healthcare provider if the patient takes medication for indigestion, heartburn, or ulcers.

• Disclose if the patient has an infection, condition, or adrenal insufficiency.

• Inform the healthcare provider if the patient is pregnant or planning to become pregnant.

• Refrain from breastfeeding while taking Levoketoconazole and for one day after the final dose.

• Levoketoconazole may cause fertility problems; discuss with the healthcare provider if one plans to have children.

• Ask the healthcare provider about the safe use of alcoholic beverages while taking Levoketoconazole.

How Is Levoketoconazole Administered?

Baseline Assessments Before Starting Levoketoconazole

• Conduct baseline liver tests (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin) before initiating Levoketoconazole treatment.

• Evaluate risks and benefits for patients with elevated AST or ALT (above normal but less than or equal to three times the upper limit).

• Obtain a baseline electrocardiogram (ECG).

• It is important to correct hypokalemia and hypomagnesemia before starting Levoketoconazole.

Dosage Initiation, Adjustment, and Monitoring for Effectiveness

• Initiate treatment with an oral dosage of 150 mg (milligrams) twice daily, with or without food.

• Adjust the dosage by 150 mg daily, less frequently than every two to three weeks. It is based on 24-hour urine-free cortisol levels and patient tolerance. Monitor cortisol levels regularly until achieving a satisfactory clinical response.

• The highest recommended daily dosage is 1200 mg. It is administered at 600 mg twice daily.

• Consider reducing the dosage to 150 mg once daily for reasons of tolerability.

• Once a stable dosage is attained, monitor cortisol levels through regular urine collections at least every one to two months or as clinically indicated.

• If urine cortisol levels persist above the upper normal limit after maximum dosage or if the patient cannot tolerate Levoketoconazole, consider discontinuing Levoketoconazole and switching to an alternative therapy.

Safety Monitoring During Levoketoconazole Treatment

• Frequent monitoring of liver tests is recommended due to reported hepatotoxicity.

• Monitor liver enzymes and bilirubin weekly for the first six weeks, bi-weekly for the next six weeks, monthly for the following three months, and then as clinically indicated.

• Before each dose increase, conduct an ECG. After achieving a stable dosage, routinely monitor for QT interval effects.

• Periodically check blood potassium and magnesium levels during treatment.

• Monitor for signs of hypocortisolism through 24-hour urine-free cortisol, the patient's morning serum or plasma cortisol, and patient symptoms.

What Are the Side Effects of Levoketoconazole?

Levoketoconazole can result in side effects.

They are:

• Skin redness.

• Aching head.

• Stomach upset or pain.

• Reduced appetite.

• Pain in joints or back.

• Irregular vaginal bleeding.

• Trouble sleeping or falling asleep.

• Digestive issues like diarrhea.

• Burning or pain during urination or increased urination.

• Challenges in focusing.

• Feelings of irritability or a low mood.

• Mouth dryness.

• Dry skin.

• Hair loss.

Certain side effects can be serious. Get in touch with the doctor promptly or seek medical assistance if the patient encounters:

• Skin rash, welts (raised, red, or discolored areas on the skin ), itching, swelling of the eyes, face, lips, or tongue, breathing or swallowing difficulties, or chest pain.

• Enlargement of the arms, hands, feet, ankles, or lower legs.

• Muscle cramps, weakness, fatigue, and difficulty with bowel movements.

• Fatigue, nausea, vomiting, abdominal pain, loss of appetite, or dizziness.

• Uncommon bruising or bleeding, blood in urine, or nosebleeds.

• Issues related to sexual function in females include reduced libido and mood changes.

• Sexual difficulties in males include reduced libido (sexual drive) and inability to achieve or sustain an erection.

• Enlargement of the breasts in males.

Levoketoconazole may also cause other side effects. Contact the doctor if the patient encounters unusual problems while taking this medication.

Dietary Considerations:Discuss with the doctor the consumption of grapefruit and grapefruit juice while on this medication.

Missed Dose:Take the missed dose as soon as remember. If it is time for the next scheduled dose, skip the missed dose and maintain the regular dosing schedule. Avoid doubling the dosage to make up for a missed one.

Overdose:

If an acute accidental overdose occurs, treatment involves supportive and symptomatic measures. Administering activated charcoal may be considered within the first hour after ingestion.

Storage and Disposal:

• Store this medication in its original container, securely closed, and away from children. Keep it at room temperature, avoid excess heat and moisture, and avoid storage in the bathroom.

• Ensure that all medications are kept out of sight and reach of children, especially those in containers like weekly pill organizers, eye drops, creams, patches, and inhalers, which may not be child-resistant. To prevent accidental poisoning, always secure safety caps and promptly store the medication in a secure location, beyond the sight and reach of children.

• Dispose of unnecessary medications in a way that prevents access by pets, children, and others. Do not flush this medication down the toilet. Instead, use a medicine take-back program. Consult the pharmacist or contact the local waste management department to inquire about take-back programs. If a take-back program is unavailable, visit the FDA's Safe Disposal of Medicines website for guidance on proper disposal methods.

For Doctors:

Indication:Levoketoconazole is prescribed for managing endogenous hypercortisolemia in adults with Cushing's syndrome when surgical intervention is impractical or has not yielded a cure. It is important to note that Levoketoconazole is not sanctioned for addressing fungal infections, and its safety and efficacy in treating such infections have not been established.

Dose:The dose for Levoketoconazole:

• Initiate at 150 mg (milligrams) orally twice daily, titrating by 150 mg every two to three weeks based on cortisol levels.

• Monitor regularly, with a maximum dosage of 1200 mg/day (milligrams per day).

• Watch for hepatotoxicity, QT prolongation, and hypocortisolism.

• Adjust dosage as needed, with specific guidelines for ALT, AST, total bilirubin, and QT prolongation.

Dosing Considerations:The dosing considerations are:

• Hepatotoxicity: Serious liver issues are reported with Levoketoconazole; monitor liver tests regularly. Check liver enzymes and bilirubin weekly for the first six weeks, then adjust frequency. After dose changes, weekly monitoring is essential until a stable dosage is reached.

• QT Prolongation: Perform an ECG before each dosage escalation; maintain regular monitoring after dosage stabilization. Periodically check blood potassium and magnesium levels during treatment.

• Hypocortisolism: Periodic monitoring of 24-hour urine-free cortisol, morning cortisol, and signs of hypocortisolism during Levoketoconazole treatment.

• QT Prolongation: Temporarily halt Levoketoconazole if the QTcF interval exceeds 500 msec. After addressing contributing factors (for example, hypokalemia, hypomagnesemia, and concomitant drugs), resume Levoketoconazole at a lower dosage when the QTcF interval returns to 500 msec or less. If QT interval prolongation recurs upon restarting, permanently discontinue Levoketoconazole.

• Hypocortisolism: Decrease or temporarily stop Levoketoconazole if urine cortisol or morning cortisol levels fall below the target range, with a rapid decrease or reported signs and symptoms of hypocortisolism. Discontinue Levoketoconazole and administer exogenous glucocorticoid replacement therapy if morning cortisol levels are below target with signs and symptoms of adrenal insufficiency. Reintroduce Levoketoconazole at a reduced dosage once cortisol levels align with target ranges and signs and symptoms of hypocortisolism have been resolved. Titrate to the previous dose if the reduced dosage is well-tolerated and does not compromise clinical response.

What Are the Pharmacological Aspects of Levoketoconazole?

Pharmacodynamics:

When used at the recommended doses for Cushing’s syndrome, Levoketoconazole can lead to a moderate increase in a measure of heart electrical activity called QTc.

Mechanism: Levoketoconazole works by blocking specific steps in the production of cortisol and Testosterone, specifically targeting enzymes involved in these processes.

Pharmacokinetics:

• Absorption: After taking the medication on an empty stomach, the highest levels in the blood are reached within 1.5 to two hours. The increase in levels is more than expected based on the dose, which went from 150 mg (milligrams) to 600 mg. With repeated doses, the medication builds up in the blood.

• Effect of Food: Taking the medication with a high-fat meal causes a small increase in blood levels, but this is not considered important for the medication's effects.

• Distribution: The medication is distributed throughout the body in a way similar to water, and it mostly binds to proteins in the blood.

• Elimination: The body breaks down Levoketoconazole mainly in the liver, with a half-life of three to 4.5 hours after a single dose and four to six hours after multiple doses. About 13 percent of the medication is excreted in the urine, with most of it leaving the body through the bile into the intestines and then being expelled in the feces.

Toxicity:

The toxicity of Levoketoconazole is as follows:

Carcinogenesis: The potential for Levoketoconazole to cause cancer has not been studied. Studies with ketoconazole, a related compound, did not show any cancer-causing effects in mice or rats, even at high doses. The doses used in these studies were below the maximum recommended dose of Levoketoconazole when adjusted for body surface area.

Mutagenesis: The ability of Levoketoconazole to cause genetic mutations has not been investigated. Tests with Ketoconazole did not reveal any signs of mutagenic potential in experiments assessing dominant lethal mutations or using the Ames Salmonella microsomal activator assay.

Impairment of Fertility: In animal studies, oral Ketoconazole demonstrated an impact on fertility in both female and male rats, with the effects being dose-dependent. In female rats, doses up to 40 mg/kg (milligrams per kilogram) of Ketoconazole (lower than the maximum recommended dose for Levoketoconazole) had no impact on fertility. However, doses of more than or equal to 75 mg/kg of Ketoconazole (equivalent to the maximum recommended dose for Levoketoconazole) reduced the pregnancy rate and the number of implantation sites. In male rats, doses as low as 24 mg/kg/day (milligrams per kilogram per day) of Ketoconazole (lower than the maximum recommended dose for Levoketoconazole) led to decreased fertility, with changes in sperm characteristics and testicular structure. In male beagle dogs, an oral dose of 25 mg/kg/day of Ketoconazole (at the maximum recommended dose for Levoketoconazole) for up to four weeks resulted in temporary effects on sperm quality and testicular size, which returned to normal after treatment was stopped.

Clinical Studies:

The effectiveness of Levoketoconazole in treating Cushing's syndrome was assessed through the following study.

Design: This study comprises an open-label dose adjustment and maintenance phase lasting up to 19 weeks, followed by an eight-week double-blind, placebo-controlled randomized withdrawal phase.

Participants: 84 patients with persistent or recurrent Cushing's syndrome, including those who had undergone surgery, prior medical treatment, and untreated cases, were enrolled.

Baseline: The average age was 45, with 76 percent female. Most had Cushing's disease, and the mean time since diagnosis was 63 months. Baseline hormone levels indicated active Cushing's syndrome.

Treatment Phases:

• Dose Titration and Maintenance (14 to 19 Weeks): Patients started at 150 mg (milligrams) orally twice daily, titrated every two weeks, and up to 600 mg twice daily to achieve normal hormone levels.

• Randomized Withdrawal (Approximately Eight Weeks): 44 patients, having stabilized during the previous phase, were randomly assigned to continue Levoketoconazole or receive a placebo.

Results: Among patients initially achieving normal hormone levels, 52.4 percent on Levoketoconazole maintained normalization compared to 5.6 percent on placebo at the end of the withdrawal phase. This study supports Levoketoconazole efficacy in normalizing hormone levels in Cushing's syndrome patients.

What Are the Contraindications of Levoketoconazole?

Levoketoconazole should not be used in individuals:

• With Liver Conditions: This includes cirrhosis, acute liver disease, or poorly controlled chronic liver disease, with elevated baseline AST or ALT exceeding three times the normal limit, recurrent symptomatic cholelithiasis, drug-induced liver injury due to Ketoconazole or any Azole antifungal therapy requiring treatment discontinuation, or extensive metastatic liver disease.

• Taking Medications Causing QT Prolongation: Individuals taking drugs linked to QT prolongation associated with ventricular arrhythmias, including torsades de pointes.

• Having Prolonged Qtcf Interval: Individuals with a baseline QTcF interval exceeding 470 msec, a history of torsades de pointes, ventricular fibrillation, ventricular tachycardia, or long QT syndrome, including those with a first-degree family history.

• Hypersensitivity: Individuals with a known hypersensitivity to Levoketoconazole, Ketoconazole, or any ingredient in Levoketoconazole.

• Taking Specific Drugs: Individuals taking drugs sensitive to CYP3A4 or both CYP3A4 and P-gP.

Warnings and Precautions:Hypocortisolism and Adrenal Insufficiency:

• Levoketoconazole may lower cortisol levels, leading to hypocortisolism.

• Adrenal insufficiency occurred in seven percent of patients during the clinical program.

• Symptoms of lowered cortisol levels include dizziness, fatigue, nausea, vomiting, loss of appetite, and abdominal pain.

• Monitor urine-free cortisol, morning blood cortisol, and symptoms periodically.

• Adjust or temporarily discontinue Levoketoconazole if cortisol levels fall below the target range or signs of hypocortisolism appear.

• Stop Levoketoconazole and administer synthetic glucocorticoid replacement therapy if morning cortisol levels are below the target range with signs of adrenal insufficiency.

• The following cessation, cortisol suppression might endure beyond the four to six-hour half-life of Levoketoconazole.

• Restart Levoketoconazole at a lower dosage when cortisol levels are within target ranges and symptoms have resolved.

Hypersensitivity Reactions:

• Hypersensitivity reactions, reported in one percent of patients, include anaphylaxis.

• Levoketoconazole is contraindicated in patients with known hypersensitivity to Levoketoconazole, Ketoconazole, or any Levoketoconazole component.

Risks Related to Decreased Testosterone:

• Levoketoconazole may lower serum testosterone in both men and women.

• Clinical manifestations in men may include gynecomastia, impotence, and oligospermia.

• Women may experience decreased libido and mood changes.

• Inform patients of symptoms related to low testosterone and encourage them to reach out to their healthcare provider if these symptoms manifest.

What Are the Drug Interactions of Levoketoconazole?

Levoketoconazole may interact with various drugs, affecting their metabolism and potentially leading to adverse effects. Here are some notable drug interactions:

QT-Prolonging Drugs:

• Clinical Impact: Increases the risk of QT prolongation and torsades de pointes.

• Prevention or Management: Contraindicated with drugs causing QT prolongation. Examples include Bosutinib, Cisapride, Clarithromycin, and Crizotinib.

Sensitive CYP3A4 Substrates:

• Clinical Impact: Raises plasma concentrations, enhancing the risk of adverse reactions.

• Prevention or Management: Contraindicated or not recommended with drugs like Alfentanil, Avanafil, Buspirone, and Conivaptan.

CYP3A4 Substrate (Atorvastatin):

• Clinical Impact: Increases plasma concentration, elevating the risk of Atorvastatin-associated myopathy.

• Prevention or Management: This may require a dose reduction of Atorvastatin. Monitor for adverse reactions.

OCT2 and MATE Substrate (Metformin):

• Clinical Impact: It raises plasma concentration, increasing the risk of metformin's adverse reactions.

• Prevention or Management: Monitor glycemia, kidney function, and vitamin B12 during Levoketoconazole titration. Adjust the metformin dosage as needed.

Strong CYP3A4 Inhibitors:

• Clinical Impact: Increases Levoketoconazole plasma concentrations, raising the risk of adverse reactions.

• Prevention or Management: Avoid administration of strong CYP3A4 inhibitors with Levoketoconazole. Discontinue use two weeks before and during Levoketoconazole treatment. For example, Ritonavir, Ritonavir-boosted Darunavir, Ritonavir-boosted Fosamprenavir, Saquinavir, glucocorticoid, and progesterone receptor antagonists (Mifepristone).

Strong CYP3A4 Inducers:

• Clinical Impact: Decreases Levoketoconazole plasma concentrations, reducing Levoketoconazole efficacy.

• Prevention or Management: Avoid administration of strong CYP3A4 inducers with Levoketoconazole. Discontinue use two weeks before and during Levoketoconazole treatment. Examples are Antibacterials (Isoniazid, Rifabutin, Rifampicin), anticonvulsants (Carbamazepine, Phenytoin), antivirals (Efavirenz, Nevirapine), and cytotoxic agents (Mitotane).

Gastric Acid Neutralizers:

• Clinical Impact: Impairs Levoketoconazole absorption from Levoketoconazole.

• Prevention or Management: Take gastric acid neutralizers, for example, Aluminum hydroxide, at least two hours after Levoketoconazole dosing.

Gastric Acid Suppressors:

• Clinical Impact: Impairs Levoketoconazole absorption.

• Prevention or Management: Avoid gastric acid suppressors with Levoketoconazole. Examples are H2-receptor antagonists, proton pump inhibitors, and Sucralfate.

Specific Considerations:

Pregnancy:

• Levoketoconazole data on birth defects is insufficient.

• Untreated Cushing’s syndrome poses risks.

• Animal studies on Ketoconazole showed potential risks at or below recommended human doses.

Lactation:

• There is limited data on Levoketoconazole in human milk.

• Advised against breastfeeding during and one day after Levoketoconazole treatment.

Females and Males of Reproductive Potential:

Infertility:

• Levoketoconazole may reduce testosterone levels and affect fertility.

• Levoketoconazole tablets lowered serum testosterone, and levels returned to baseline upon discontinuation.

• Clinical manifestations may include gynecomastia, impotence, and oligospermia.

• In fertility studies, oral Levoketoconazole impaired fertility in rats and targeted reproductive tissues in male dogs.

Pediatric Use: Safety and effectiveness are not established in patients below 18 years.

Geriatric Use: Limited data in patients 65 years and older. Response differences have yet to be determined.

Renal Impairment: No experience with Levoketoconazole in renal impairment. Pharmacokinetics is similar to healthy subjects.

Hepatic Impairment: Contraindicated in patients with poorly controlled chronic liver disease, acute liver disease, cirrhosis, recurrent symptomatic cholelithiasis, prior drug-induced liver injury due to Ketoconazole, or extensive metastatic liver disease.