Ketoconazole - Battling Tinea Corporis with Effective Antifungal Therapy

Overview

Ketoconazole, a synthetic antifungal drug, was developed in the 1970s. Initially used to treat various fungal infections, it later gained recognition for inhibiting hormone production in the body. It was approved by the U.S. Food and Drug Administration (FDA) in 2000. This expanded its applications to conditions like Cushing's syndrome, androgenetic alopecia, and hirsutism. It is available in topical and oral forms, though oral use has been restricted due to safety concerns and drug interactions. Ketoconazole remains an essential treatment for fungal infections, while ongoing research explores its potential in other medical contexts, such as cancer therapy and anti-inflammatory applications.

Drug Group:

Ketoconazole belongs to the drug group known as antifungals.

Available Doses and Dosage Forms:

Ketoconazole is available in several formulations, making it adaptable to the specific needs of patients. These include:

1. Topical Creams and Shampoos: For mild to moderate cases of Tinea corporis, topical Ketoconazole (one or two percent strength) creams or shampoos are often the go-to treatment. Applying them directly to the affected skin offers precise relief with ease.

2. Oral Tablets: In more severe or widespread cases of tinea corporis, oral Ketoconazole tablets available in strength of 200 to 400 mg (milligrams) may be prescribed. These are systemic treatments that can reach the infection through the bloodstream, offering a comprehensive approach to healing.

For Patients

What Is Tinea Corporis?

Tinea corporis, often called ringworm, is a fungal skin infection. Despite its name, it has nothing to do with worms. This infection is caused by various types of dermatophyte fungi, typically belonging to the genera Trichophyton or Microsporum. Tinea corporis manifests as a red, circular rash on the skin that is often raised at the edges, giving it a ring-like appearance, hence the name ringworm.

This contagious infection can spread through direct skin-to-skin contact with an infected individual or by coming into contact with contaminated objects or surfaces. Common symptoms include itching, redness, and scaling of the affected skin. Tinea corporis can affect people of all ages and is more prevalent in warm and humid environments.

Treatment typically involves the application of antifungal creams or ointments directly to the affected area. In certain instances, healthcare providers may recommend oral antifungal medications, particularly when the infection is extensive or severe. Good hygiene practices and avoiding sharing personal items can help prevent the spread of tinea corporis. If the infection persists or worsens, seeking advice from a medical practitioner is crucial to receive an accurate diagnosis and appropriate treatment.

How Does Ketoconazole Work?

Ketoconazole functions as an antifungal medication by blocking the growth and reproduction of fungi. Its primary mechanism of action is to interfere with the synthesis of ergosterol, a crucial component of fungal cell membranes. Here is how Ketoconazole works:

• Inhibition of Ergosterol Synthesis: Fungi, including the ones responsible for fungal infections, require ergosterol to maintain the integrity and function of their cell membranes. Ketoconazole inhibits an enzyme called lanosterol 14 alpha-demethylase, which is essential for the conversion of lanosterol and ergosterol. By blocking this enzyme, Ketoconazole disrupts ergosterol synthesis, weakening the fungal cell membrane.

• Alteration of Membrane Permeability: As ergosterol production decreases, the fungal cell membrane becomes less stable and more permeable. This change in membrane structure affects the fungi's ability to regulate ions and molecules, leading to a loss of essential nutrients and cellular components.

• Cell Death: The altered cell membrane's increased permeability can ultimately lead to cell death. With compromised membranes, fungal cells are unable to maintain their structural integrity, and they become more susceptible to environmental stressors and immune system attacks.

• Reduction of Fungal Growth: By disrupting ergosterol synthesis and weakening fungal cell membranes, Ketoconazole effectively slows down or stops the growth and multiplication of fungal organisms. This helps control and eliminate fungal infections.

What Is the Dosage of Ketoconazole?

1. Oral Ketoconazole Tablets:

• For most fungal infections, the typical adult dose is 200 to 400 milligrams (mg) once daily. The prescribed amount may fluctuate based on the seriousness of the infection and the specific recommendation of the prescribing healthcare provider.

• It is usually taken with a meal to improve absorption.

• Treatment duration varies, but it typically lasts several weeks.

2. Topical Cream or Gel (For Skin Infections):

• Apply a thin layer of Ketoconazole cream or gel to the affected area once or twice daily, as directed by the doctor.

• Continue the treatment for the recommended period, even if the symptoms improve before that time.

3. Shampoo (For Fungal Infections of the Scalp):

• Gently apply a small quantity of Ketoconazole shampoo onto damp hair and scalp.

• Massage it in and leave it on for a few minutes before rinsing thoroughly.

• The frequency of use may vary, but it is typically used every three to four days for a few weeks.

How Effective Is Ketoconazole?

The effectiveness of Ketoconazole in treating tinea infections can vary depending on several factors, including the type and severity of the infection, as well as individual response to the medication. No specific percentage success rates universally apply to all cases of tinea treated with Ketoconazole. However, Ketoconazole is generally considered effective in many cases of tinea infections.

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

Before using Ketoconazole, please take note of the following:

• Inform the doctor and pharmacist about any allergies one has, especially if one is allergic to Ketoconazole, any other medications, or any ingredients in Ketoconazole tablets. Refer to the medication guide or consult the pharmacist for a list of ingredients.

• Let the doctor know if one is currently taking any of the following medications, as they may interact with Ketoconazole: Alprazolam, Eplerenone, ergot alkaloids such as Ergotamine, Dihydroergotamine, and Methylergonovine, Felodipine, Irinotecan, Lovastatin, Lurasidone, Midazolam, Nisoldipine, Simvastatin, Tolvaptan and Triazolam.

• Share the complete list of prescription and non-prescription medications, vitamins, dietary supplements, and herbal products with the doctor and pharmacist. Some examples include Aliskiren, anticoagulants (blood thinners) like Dabigatran, Rivaroxaban, and Warfarin, Aprepitant, Aripiprazole, Atorvastatin, Bosentan, Budesonide, Buspirone, Carbamazepine, calcium channel blockers such as Amlodipine, Diltiazem, Nicardipine, Nifedipine, and Verapamil, cancer medications including Bortezomib, Busulfan, Dasatinib, Docetaxel, Erlotinib, Ixabepilone, Lapatinib, Nilotinib, Paclitaxel, Trimetrexate, Vincristine, Vinblastine, and Vinorelbine, Ciclesonide, Cilostazol, Cinacalcet, Colchicine, Dexamethasone, Digoxin, Eletriptan, Fentanyl, Fesoterodine, Fluticasone, Haloperidol, HIV (human immunodeficiency virus) medications like Darunavir, Efavirenz, Fosamprenavir, Indinavir, Maraviroc, Nevirapine, Ritonavir, and Saquinavir, immunosuppressants like Cyclosporine, Everolimus, Sirolimus, and Tacrolimus, Imatinib, medications for erectile dysfunction such as Sildenafil, Tadalafil, and Vardenafil, medications for indigestion, heartburn, or ulcers like Cimetidine, Famotidine, Lansoprazole, Nizatidine, Omeprazole, and Ranitidine, medications to treat tuberculosis such as Isoniazid, Rifabutin, Rifampin, Methylprednisolone, Nadolol, Oxycodone, Phenytoin, Praziquantel, Quetiapine, Ramelteon, Repaglinide, Risperidone, Salmeterol, Saxagliptin, Solifenacin, immunosuppressants such as Cyclosporine, Sirolimus, and Tacrolimus, Tamsulosin, Telithromycin and Tolterodine. The doctor may need to adjust the medication doses or closely monitor for potential side effects. Many other medications can interact with Ketoconazole, so ensure that the doctor is aware of all the medications, even those not listed here.

• If one is taking an antacid containing aluminum, calcium, or magnesium, take it either one hour before or two hours after taking Ketoconazole.

• Inform the doctor if one has or has had conditions like adrenal insufficiency (a condition characterized by inadequate production of steroid hormones by the adrenal glands).

• If one is pregnant, planning to become pregnant, or breastfeeding, inform the doctor.

• If there are any upcoming surgeries, including dental procedures, inform the surgeon or dentist that the patient is taking Ketoconazole.

• Please note that drinking alcoholic beverages, including wine and beer, and medications containing alcohol, such as cough syrup, while using Ketoconazole can heighten the risk of liver damage. Additionally, it may result in adverse effects such as flushing, rash, nausea, headaches, and swelling in the hands, feet, ankles, or lower legs. It is advisable to avoid alcohol while on Ketoconazole.

How Is Ketoconazole Administered?

Ketoconazole is administered in the following ways:

• Ketoconazole is typically administered as an oral tablet, usually taken once a day. It is essential to maintain a consistent daily schedule for taking Ketoconazole. To ensure safe and effective usage, carefully follow the instructions on the prescription label, and do not hesitate to seek clarification from the doctor or pharmacist regarding any uncertainties. Adhere to the prescribed dosage precisely; do not exceed or reduce it or take it more frequently than advised by the physician.

• If the condition does not show improvement, the doctor may consider increasing the dosage.

• It might be necessary to continue taking Ketoconazole for an extended period, possibly up to six months or more, to completely eradicate the infection. Continue taking Ketoconazole until the doctor instructs the patient to stop, even if one starts feeling better. Do not discontinue Ketoconazole without consulting the doctor, as prematurely stopping the medication could result in the infection returning shortly after cessation.

What Are the Side Effects of Ketoconazole?

Ketoconazole may lead to side effects. If one experiences any of the following symptoms and they are severe or persistent, inform the doctor:

• Headache.

• Stomach pain.

• Diarrhea.

• Constipation.

• Heartburn.

• Gas.

• Changes in the ability to taste food.

• Dry mouth.

• Alterations in tongue color.

• Difficulty falling asleep or staying asleep.

• Nervousness.

• Sensations of numbness, burning, or tingling in the hands or feet.

• Muscle pain.

• Hair loss.

• Flushing.

• Chills.

• Sensitivity to light.

• Nosebleeds.

• Breast enlargement in males.

• Decrease in sexual ability.

While uncommon, certain side effects can be serious. They are as follows:

• Rash.

• Hives.

• Itching.

• Swelling of the eyes, face, lips, tongue, hands, feet, ankles, or lower legs.

• Hoarseness.

• Difficulty breathing or swallowing.

• Tiredness or weakness.

Ketoconazole may also reduce the production of sperm in men, especially at high doses. If a man plans to have children, discuss the potential risks of taking this medication with the doctor.

Dietary Considerations:

None, unless specified by the doctor.

Missed Dose:

In case of a missed dose, take it when remembering. However, if it is nearly time for the next dose, skip the one that is missed and maintain the regular dosing schedule. Refrain from taking a double dose to compensate for any missed doses.

Overdose:

If an acute accidental overdose occurs, treatment involves supportive and symptomatic measures. Activated charcoal may be administered within the initial hour after ingestion.

Storage:

Storage Instructions:

• Keep this medication in its original container.

• Ensure the container is tightly closed.

• Store the medication at room temperature.

• Avoid exposing it to excess heat and moisture (refrain from storing it in the bathroom).

Safety Tips:

• Store the medication in a place that is out of children's reach.

• Take note that several container types, such as weekly pill organizers, as well as those designed for eye drops, creams, patches, and inhalers, lack child-resistant features and can be effortlessly accessed by small children.

• Always secure safety caps promptly and store medications in a secure location, hidden from children's sight and reach.

Disposal Guidelines:

• Dispose of any unused medications properly to prevent accidental ingestion by pets, children, or others.

• Do not flush this medication down the toilet.

• The recommended method for disposing of this medication is through a medicine take-back program.

• One can inquire about available take-back programs in the community by consulting the pharmacist or contacting the local waste disposal or recycling department.

For Doctors:

Indication:

Ketoconazole is prescribed for the management of fungal infections. Its specific indications include

1. Superficial Fungal Infections: Ketoconazole is used to treat various skin, hair, and nail infections caused by fungi. Common examples include the following.

• Tinea infections (for example, athlete's foot, ringworm).

• Fungal infections affect the skin and mucous membranes.

• Fungal infections of the nails (onychomycosis).

2. Seborrheic Dermatitis: Ketoconazole is successful in alleviating seborrheic dermatitis, a persistent skin condition characterized by dry, flaky skin, frequently impacting the scalp (commonly known as dandruff).

3. Systemic Fungal Infections: In some cases, Ketoconazole might be employed for the treatment of systemic fungal infections, which are infections that can affect internal organs or the bloodstream. These infections are often more severe and may include:

• Invasive candidiasis.

• Certain endemic mycoses (fungal infections associated with specific geographic regions).

• Fungal infections in immunocompromised individuals.

4. Off-Label Uses: Apart from its authorized uses, Ketoconazole has been employed off-label for various conditions. These include addressing Cushing's syndrome, a hormonal disorder, and serving as a supplementary therapy in prostate cancer treatment. However, its utilization for these purposes has dwindled due to safety apprehensions and the existence of alternative treatment options.

Dose: Ketoconazole is available in various doses and dosage forms, including:

• Oral Tablets: Ketoconazole tablets are available in strengths such as 200 mg. This is a common form of systemic fungal infection.

• Topical Creams: Ketoconazole cream is available in concentrations like two percent. This form is used for treating fungal skin infections.

• Shampoos: Ketoconazole shampoo is available in concentrations like one to two percent. Its primary application lies in the treatment of fungal infections affecting the scalp, including conditions like dandruff and seborrheic dermatitis.

• Foam and Gel: These are topical formulations used for fungal skin infections and seborrheic dermatitis.

• Oral Suspension: This is a liquid form of Ketoconazole that may be used in specific cases.

• Suppositories: In some cases, Ketoconazole may be available in suppository form for certain fungal infections.

Dosing Considerations:

• Age: Dosing often varies by age group. Pediatric and elderly patients may require adjusted doses due to differences in metabolism and the potential for side effects.

• Weight: Some medications are dosed based on a patient's weight, especially in pediatrics.

• Gender: In some cases, gender differences can affect dosing.

What Are the Pharmacological Aspects of Ketoconazole?

1. Pharmacodynamics: Ketoconazole (an antifungal medication) works by disrupting fungal cell membranes through the inhibition of ergosterol synthesis. It has broad-spectrum activity against a variety of fungi. The drug's effectiveness depends on maintaining sufficient drug levels in the body and typically requires several weeks of treatment. Some fungi can develop resistance to Ketoconazole over time. It comes in various forms for different types of fungal infections and may interact with other medications due to its impact on liver enzymes.

2. Mechanism: Ketoconazole hinders the creation of ergosterol, a critical element in the fungal cell membrane, by inhibiting the cytochrome P-450-dependent enzyme called lanosterol 14α-demethylase. This enzyme is responsible for transforming lanosterol into ergosterol within the fungal cell membrane. Consequently, this inhibition leads to the buildup of methylated sterol precursors and a decrease in ergosterol levels within the cell membrane. As a result, the structure and function of the fungal cell membrane are compromised.

3. Pharmacokinetics

• Absorption: Ketoconazole, a weak dibasic agent, needs acidity for absorption. Taking a 200 mg dose with food leads to peak plasma concentrations of about 3.5 µg/mL within one to two hours.

• Distribution: Ketoconazole binds mainly to albumin in plasma (about 99 percent) but reaches cerebrospinal fluid in minimal amounts.

• Metabolism: CYP3A4 is the primary enzyme involved in Ketoconazole's metabolism. It is converted into inactive metabolites through various pathways.

• Elimination: Plasma elimination has two phases, with a two-hour half-life initially and eight hours later. About 13 percent of the dose is excreted in urine, with a small portion unchanged. The major route is through bile into the intestinal tract, with around 57 percent excreted in feces.

Toxicity:

The toxicity of Ketoconazole is given below.

• Carcinogenicity, Mutagenicity, and Fertility Impairment: Ketoconazole was not mutagenic in tests for genetic mutations or carcinogenic in studies on mice and rats. In these studies, even the highest doses were not significantly greater than human clinical doses when adjusted for body surface area.

• Pregnancy Category C: Ketoconazole has shown teratogenic effects in rats when given at high doses (80 mg/kg/day), but these effects may be related to maternal toxicity. There are no well-controlled studies in pregnant women. Ketoconazole should be administered during pregnancy solely if the prospective advantages are adjudged to surpass the conceivable perils of embryonic development.

• Nonteratogenic Effects: Ketoconazole demonstrated embryotoxicity in rats when given at doses exceeding 80 mg/kg during the initial trimester of pregnancy. Additionally, dystocia (difficult labor) was observed in rats given oral Ketoconazole during the third trimester of gestation when administered at doses higher than 10 mg/kg (about one-fourth the maximum human dose based on body surface area comparison).

Clinical Studies:

Study 1 enrolled 459 participants aged 12 and older with moderate to severe seborrheic dermatitis in a double-blind, randomized trial. Of these, 229 received Ketoconazole, and 230 received a placebo (vehicle) once daily for 14 days. Efficacy was assessed on day 28. Effective treatment meant an Investigator's Global Assessment score of less than or equal to one and specific scores for erythema and scaling. The proportion of effectively treated participants was 25.3 percent with Ketoconazole and 13.9 percent with the placebo.

Two more trials, similar in design, included 316 participants using Ketoconazole. These trials also evaluated efficacy at Day 28 by assessing the proportion of participants with complete clearance. The impact of individual components of the placebo on efficacy was not determined.

What Are the Contraindications of Ketoconazole?

The contraindications of Ketoconazole are as follows:

• CYP3A4 Substrates: Co-administration of several CYP3A4 substrates, including Dofetilide, Quinidine, Cisapride, and Pimozide, is not recommended when taking Ketoconazole Tablets. Such co-administration can lead to elevated plasma concentrations of these medications, potentially intensifying both their therapeutic and adverse effects to a degree where serious adverse reactions may occur. For instance, increased plasma concentrations of these drugs can result in QT interval prolongation, occasionally leading to life-threatening ventricular tachyarrhythmias, including torsades de pointes, a potentially fatal arrhythmia. Furthermore, the following drugs are also contraindicated when taking Ketoconazole tablets: Methadone, Disopyramide, Dronedarone, ergot alkaloids (such as Dihydroergotamine, Ergometrine, Ergotamine, Methylergometrine), Irinotecan, Lurasidone, oral Midazolam, Alprazolam, Triazolam, Felodipine, Nisoldipine, Ranolazine, Tolvaptan, Eplerenone, Lovastatin, Simvastatin, and Colchicine.

• Enhanced Sedation: Co-administering Ketoconazole tablets with oral Midazolam, oral Triazolam, or Alprazolam has led to increased plasma concentrations of these drugs. This can amplify and prolong their hypnotic and sedative effects, particularly with repeated dosing or chronic use of these agents. Therefore, concurrent use of Ketoconazole tablets with oral Triazolam, oral Midazolam, or Alprazolam is not recommended.

• Myopathy: Co-administration of Ketoconazole tablets with HMG-CoA reductase inhibitors metabolized by CYP3A4, such as Simvastatin and Lovastatin, is not recommended.

• Ergotism: Simultaneous use of ergot alkaloids, including Dihydroergotamine and Ergotamine, with Ketoconazole tablets, is contraindicated.

• Liver Disease: Ketoconazole tablets should not be used by patients with acute or chronic liver disease.

• Hypersensitivity: Ketoconazole is contraindicated for individuals who have demonstrated hypersensitivity to the drug.

Warnings and Precautions:

The warning and precautions associated are as follows:

1. Usage in Specific Cases:

• Ketoconazole tablets should only be considered when alternative effective antifungal treatments are unavailable or cannot be tolerated and when the potential advantages are adjudged to predominate over the potential hazards.

2. Hepatotoxicity:

• Oral Ketoconazole has been associated with severe hepatotoxicity, including cases that led to fatality or necessitated liver transplantation. In some cases, there were no obvious risk factors for liver disease among patients. Severe hepatotoxicity has been documented both in individuals who received high doses for brief periods and in those taking lower doses over extended periods. Hepatic damage is generally, but not always, reversible upon discontinuation of Ketoconazole tablet treatment. Cases of hepatitis have been documented in children.

• Prior to commencing treatment, conducting baseline laboratory tests is crucial. These tests should encompass SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and screening for viral hepatitis. Patients should be counseled against alcohol consumption during their course of treatment, and whenever feasible, the use of other substances that may harm the liver should be avoided.

• Vigilant monitoring for liver injury is crucial. During treatment, serum ALT levels should be assessed weekly throughout the treatment course. If ALT values rise above the upper limit of normal or exceed 30 percent above baseline, or if the patient experiences symptoms, Ketoconazole treatment should be halted, and a comprehensive set of liver tests should be conducted. Liver tests should be repeated to ensure that values return to normal. It is noteworthy that hepatotoxicity has been reported upon reinitiating oral Ketoconazole. Should a decision be made to restart oral Ketoconazole, frequent monitoring of the patient is necessary to identify any recurring liver injury caused by the medication.

3. QT Prolongation and Drug Interactions Leading to QT Prolongation:

• Ketoconazole can extend the QT interval. Co-administration of Ketoconazole with specific drugs is contraindicated due to their potential to further protract the QT interval, such as Dofetilide, Quinidine, Pimozide, Cisapride, Methadone, Disopyramide, Dronedarone, and Ranolazine. This combination can raise plasma concentrations of these drugs, possibly leading to a prolonged QT interval and severe ventricular dysrhythmias like torsades de pointes.

4. Adrenal Insufficiency:

• Ketoconazole tablets can lower adrenal corticosteroid production at doses of 400 mg and higher. This effect is unique to Ketoconazole among azole drugs. It is recommended to adhere to the prescribed daily dosage range of 200 mg to 400 mg. Patients with adrenal insufficiency, borderline adrenal function, or those undergoing extended periods of stress (for example, major surgery or intensive care) should have their adrenal function monitored closely.

What Are the Drug Interactions of Ketoconazole?

The drug interactions are as follows: Ketoconazole primarily undergoes metabolism through CYP3A4. Compounds that either participate in the same metabolic pathway or exert an influence on CYP3A4 enzyme activity can have an impact on the pharmacokinetics of Ketoconazole. Conversely, Ketoconazole may alter the pharmacokinetics of substances that share this metabolic route. Ketoconazole acts as a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When co-administering medications, consult the respective label for information regarding metabolism and potential dosage adjustments. Interaction studies have only been conducted in adults, and the relevance of these results for pediatric patients remains unknown.

• Drugs That May Decrease Ketoconazole Plasma Concentrations: Drugs that decrease stomach acidity, such as acid-neutralizing medications like Aluminum hydroxide or acid-suppressing drugs like H2-receptor antagonists and proton pump inhibitors, can hinder the absorption of Ketoconazole from tablets. These drugs should be used cautiously alongside Ketoconazole tablets:

1. Ketoconazole tablets should be taken with an acidic beverage (for example, non-diet cola) when co-administered with drugs that reduce gastric acidity.

2. Acid-neutralizing medicines (for example, aluminum hydroxide) should be taken at least one hour before or two hours after Ketoconazole tablets.

3. During co-administration, monitor antifungal activity and adjust the Ketoconazole tablets dose as necessary.

• Coadministration of Ketoconazole Tablets With Potent Enzyme Inducers of CYP3A4: Potent enzyme inducers of CYP3A4, such as Isoniazid, Rifabutin, Rifampicin, Carbamazepine, Phenytoin, Efavirenz, and Nevirapine, may decrease the bioavailability of Ketoconazole to an extent that reduces its effectiveness. Avoid the use of these drugs from two weeks before and during Ketoconazole tablet treatment unless the benefits outweigh the risk of reduced Ketoconazole efficacy. Monitor antifungal activity upon coadministration and adjust the Ketoconazole tablets dose as needed.

• Drugs That May Increase Ketoconazole Plasma Concentrations: Potent inhibitors of CYP3A4, such as Ritonavir, Ritonavir-boosted Darunavir, and Ritonavir-boosted Fosamprenavir, can elevate the bioavailability of Ketoconazole. Use these drugs cautiously when co-administered with Ketoconazole tablets. Monitor patients closely for signs of increased or prolonged effects of Ketoconazole and adjust the Ketoconazole tablet dose as necessary. Measure Ketoconazole plasma concentrations when appropriate.

• Drugs That May Have Their Plasma Concentrations Increased by Ketoconazole: Ketoconazole inhibits the metabolism and drug transport by P-glycoprotein of drugs metabolized by CYP3A4, potentially leading to increased plasma concentrations and effects of these drugs and/or their active metabolites. Drugs metabolized by CYP3A4 and recognized for their QT interval-prolonging effects might not be advisable when used together with Ketoconazole tablets, as this combination could result in ventricular tachyarrhythmias, including torsade de pointes, a potentially fatal arrhythmia.

Specific Considerations:

• Patients with Hepatic or Renal Impairment: For individuals experiencing liver or kidney dysfunction, the pharmacokinetics of Ketoconazole showed no significant differences compared to healthy individuals.

• Pediatric Patients: Limited data on the pharmacokinetics of Ketoconazole tablets are available for pediatric patients. Detectable levels (3 to 10 mg/kg) of Ketoconazole in the bloodstream have been noted in premature infants and pediatric patients aged five months and older (3 to 13 mg/kg) when the drug was given as a suspension, tablet, or crushed tablet. Absorption may be higher when administered as a suspension compared to a crushed tablet. Conditions that increase gastric pH may affect absorption.

• Electrocardiogram: Pre-clinical studies have shown that Ketoconazole can affect cardiac electrical activity by inhibiting a component of the cardiac potassium current. This prolongs the action potential duration and may lead to a longer QTc interval. Clinical research indicates that administering oral Ketoconazole at a dosage of 200 mg twice a day for three to seven days can lead to an extension of the QTc interval. On average, this extension ranges from approximately six to 12 milliseconds and typically happens within one to four hours after the medication is taken.