Ketoconazole (Tablets, Shampoo, Suppositories) Instructions for Use

ATC Code

G01AF11 (Ketoconazole)

Active Substance

Ketoconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antimicrobial agents and antiseptics used in gynecology; antimicrobial agents and antiseptics, except combinations with corticosteroids; imidazole derivatives

Pharmacological Action

Antifungal agent. It has fungicidal and fungistatic action. The mechanism of action consists in the inhibition of ergosterol synthesis and alteration of the lipid composition of the membrane. It is active against the causative agent of tinea versicolor Malassezia furfur, causative agents of some dermatomycoses ( Trichophyton, Epidermophyton floccosum, Microsporum), causative agents of candidiasis ( Candida), as well as causative agents of systemic mycoses ( Cryptococcus).

It is also active against gram-positive cocci: Staphylococcus spp., Streptococcus spp.

Pharmacokinetics

Ketoconazole is a weak dibasic compound that dissolves and is absorbed in an acidic environment. The C_max of ketoconazole in plasma is about 3.5 µg/ml and is reached 1-2 hours after a single oral dose of 200 mg with a meal. The bioavailability of ketoconazole is maximal when taken with food. The absorption of ketoconazole is reduced in patients with reduced gastric acidity, for example, those taking antacid drugs such as aluminum hydroxide, and antisecretory drugs such as histamine H₂-receptor blockers and proton pump inhibitors, as well as in patients with achlorhydria caused by a certain disease.

Plasma protein binding, mainly to the albumin fraction, is 99%. Ketoconazole is widely distributed in tissues, but only a small part of the drug penetrates into the cerebrospinal fluid.

After absorption from the gastrointestinal tract, Ketoconazole is metabolized in the liver to form a large number of inactive metabolites.

In vitro studies have shown that the isoenzyme CYP3A4 is involved in the metabolism of ketoconazole. The main pathways of metabolism are oxidation and cleavage of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. Ketoconazole is not an inducer of its own metabolism. Elimination from plasma is biphasic: during the first 10 hours T_1/2 is 2 hours, subsequently – 8 hours.

About 13% is excreted in the urine, of which 2-4% is unchanged. It is excreted mainly with bile into the gastrointestinal tract and about 57% is excreted in the feces.

Indications

For external use: treatment and prevention of fungal infections of the scalp skin; dermatomycosis of smooth skin; tinea cruris; tinea of hands and feet, skin candidiasis.

For topical use: treatment of acute and chronic recurrent vaginal candidiasis; prevention of fungal infections of the vagina with reduced body resistance and during treatment with antibacterial agents and other drugs that disrupt the normal vaginal microflora.

For oral administration (when other methods of therapy are unavailable and intolerant): blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis.

ICD codes

Dosage Regimen

Adhere strictly to the prescribed dosage form and indication.

For vaginal suppositories: Insert one suppository intravaginally, preferably at bedtime. Continue treatment for the full prescribed course, typically 3 to 14 days, even if symptoms improve.

For shampoo (2%): Apply to wet hair. Lather and leave on the scalp for 3-5 minutes. Rinse thoroughly. Use twice weekly for 2-4 weeks, with at least 3 days between applications. For pityriasis versicolor, apply to affected skin, leave for 5 minutes, and rinse. Use daily for up to 5 days.

For oral tablets: Administer with a meal to ensure maximal absorption.

For adults and children over 30 kg: The typical dose is 200 mg to 400 mg once daily.

For children under 30 kg: The dose is 4 mg to 8 mg per kg of body weight once daily.

Do not exceed the maximum daily dose of 400 mg for children or 800 mg for adults in severe infections.

The duration of systemic therapy depends on the infection and clinical response; it may extend for weeks or months. Monitor liver function before and during treatment.

Adverse Reactions

From the nervous system headache, dizziness, paresthesia, drowsiness, increased excitability, insomnia, anxiety, fatigue, general weakness, reversible increase in intracranial pressure (for example, papilledema, bulging fontanelle in young children).

From the digestive system nausea, abdominal pain, diarrhea, impaired liver function, vomiting, dyspepsia, constipation, dry mouth, dysgeusia, flatulence, tongue discoloration, toxic hepatitis (increased activity of hepatic transaminases or alkaline phosphatase, jaundice, severe hepatotoxicity, including cholestatic hepatitis, hepatonecrosis (biopsy), liver cirrhosis, liver failure (including cases of transplantation and death).

From the metabolism: alcohol intolerance, anorexia, hyperlipidemia, increased appetite.

From the musculoskeletal system: myalgia, arthralgia.

From the respiratory system: nosebleed.

From the skin and subcutaneous tissue: alopecia, dermatitis, erythema, erythema multiforme, pruritus, rash, xeroderma, flushing, acute generalized exanthematous pustulosis, photosensitivity.

From the cardiovascular system: orthostatic hypotension.

From the endocrine system: gynecomastia, adrenal insufficiency, menstrual cycle disorder, possible temporary decrease in plasma testosterone concentration (normalizes within 24 hours after administration).

From the sensory organs: photophobia.

Allergic reactions rash, urticaria, anaphylactic shock, anaphylactic reactions, angioedema.

From the immune system: pseudoanaphylactic shock.

From the reproductive system: erectile dysfunction, azoospermia (at doses exceeding therapeutic – 200-400 mg/day).

From laboratory parameters: decreased number of thrombocytopenia.

General reactions: fever, peripheral edema, chills.

Contraindications

Acute and chronic liver diseases, pregnancy, lactation, children under 3 years of age, hypersensitivity to ketoconazole; simultaneous administration with the following substrates of the CYP3A4 isoenzyme (an increase in the plasma concentration of these drugs caused by co-administration with ketoconazole can lead to an increase or prolongation of both therapeutic and adverse effects and the development of potentially dangerous effects, including QT interval prolongation and the development of torsades de pointes ventricular arrhythmia): analgesics (levacetylmethadol, methadone); antiarrhythmics (disopyramide, dofetilide, dronedarone, quinidine); anthelmintic and antiprotozoal drugs (halofantrine); antihistamines (astemizole, mizolastine, terfenadine); drugs for the treatment of migraine (dihydroergotamine, ergometrine, ergotamine, methylergometrine); antitumor drugs (irinotecan); antipsychotic drugs, anxiolytics and hypnotics (lurasidone, oral midazolam, pimozide, sertindole, triazolam); calcium channel blockers (bepridil, felodipine, lercanidipine, nisoldipine); cardiovascular drugs of various groups (ivabradine, ranolazine); diuretics (eplerenone); immunosuppressants (everolimus); gastrointestinal drugs (cisapride, domperidone); hypolipidemic drugs (lovastatin, simvastatin); others (colchicine when treating patients with impaired liver and kidney function).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal dysfunction.

Pediatric Use

Contraindicated for use in children under 3 years of age.

Special Precautions

The use for fungal meningitis is not advisable, because Ketoconazole poorly penetrates the blood-brain barrier.

Due to the risk of hepatotoxicity, including Ketoconazole should be used only in cases where the potential benefit outweighs the possible risk.

In patients with elevated liver enzymes or a history of toxic liver damage due to taking other drugs, Ketoconazole should not be used, except in cases where the expected benefit justifies the risk of liver damage.

Before starting treatment, liver function should be assessed to rule out acute or chronic diseases. During treatment, it is necessary to regularly monitor the peripheral blood picture, functional state of the liver and kidneys in patients in order not to miss the first symptoms of hepatotoxicity. The development of hepatotoxicity cannot be ruled out during the first month, and even during the first week of therapy. The total dose of ketoconazole is a risk factor for severe hepatotoxicity. In this regard, it is recommended to regularly monitor liver function in patients receiving ketoconazole therapy during the treatment period.

In patients with adrenal insufficiency or borderline conditions under stress (including extensive surgical interventions, intensive care conditions), in patients with a long course of therapy with suspected adrenal insufficiency, adrenal function should be monitored, because in volunteers, Ketoconazole at a daily dose of 400 mg and more caused a decrease in the “cortisol response” to ACTH stimulation.

If glucocorticoids were used to treat skin diseases, then Ketoconazole is prescribed no earlier than 2 weeks after their withdrawal.

Consumption of acidic drinks increases the absorption of ketoconazole.

Drug Interactions

With simultaneous use of ketoconazole with antacids (aluminum hydroxide, histamine H₂-receptor blockers, proton pump inhibitors), the absorption of ketoconazole from the gastrointestinal tract is reduced. With these combinations, the antifungal activity of ketoconazole should be monitored and its dose adjusted if necessary.

With simultaneous use of ketoconazole with potent inducers of the CYP3A4 isoenzyme, a decrease in the bioavailability of ketoconazole is possible, which can cause a significant decrease in its effectiveness. Such drugs include isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine. If these combinations cannot be avoided, then the antifungal activity of ketoconazole should be monitored and its dose increased if necessary.

With simultaneous use of ketoconazole with potent inhibitors of the CYP3A4 isoenzyme (for example, antiviral drugs, including ritonavir, ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir), an increase in the bioavailability of ketoconazole is possible. With these combinations, the patient’s condition should be monitored to identify symptoms of increased intensity and duration of action of ketoconazole, the concentration of ketoconazole in blood plasma and, if necessary, reduce its dose.

With simultaneous use, Ketoconazole is able to inhibit CYP3A4-mediated metabolism of drugs, as well as the transport of active substances mediated by P-glycoprotein. This can lead to an increase in the plasma concentrations of these drugs and/or their active metabolites, which causes an increase in the intensity and duration of therapeutic or adverse effects of the concomitantly used drugs.

Simultaneous use with ketoconazole of the following drugs is not recommended: tamsulosin, fentanyl, rifabutin, rivaroxaban, carbamazepine, dasatinib, nilotinib, trabectedin, salmeterol. If these combinations cannot be avoided, then clinical monitoring of the patient’s condition should be provided to identify symptoms of increased intensity or duration of therapeutic and/or adverse effects, monitor the concentration of the drug in blood plasma and, if necessary, reduce the dose of the corresponding drug or suspend its use.

Ketoconazole should be used with caution simultaneously with the following drugs: alfentanil, buprenorphine (IV and sublingual), oxycodone, digoxin, coumarins, cilostazol, repaglinide, saxagliptin, praziquantel, ebastine, eletriptan, bortezomib, busulfan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids, alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, midazolam (IV), perospirone, quetiapine, ramelteon, risperidone, maraviroc, indinavir, saquinavir, nadolol, verapamil, aliskiren, aprepitant, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, sirolimus, tacrolimus, temsirolimus, atorvastatin, reboxetine, fesoterodine, imidafenacin, sildenafil, solifenacin, tadalafil, tolterodine, alitretinoin (oral dosage form), cinacalcet, mozavaptan, tolvaptan. With concomitant use, careful monitoring of the patient’s clinical condition is recommended, if necessary – monitoring of the drug concentration in blood plasma and if required – reducing its dose.

In isolated cases, a disulfiram-like reaction is possible when consuming alcohol while taking ketoconazole.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Over-the-Counter

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.