Mycosoral^® (Tablets, Ointment, Shampoo) Instructions for Use

ATC Code

J02AB02 (Ketoconazole)

Active Substance

Ketoconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; imidazole derivatives

Pharmacological Action

Ketoconazole is a synthetic derivative of imidazoledioxolane, possessing fungicidal or fungistatic activity against dermatophytes, yeast-like fungi (Candida, Pityrosporum, Torulopsis, Cryptococcus), dimorphic fungi, and higher fungi (eumycetes).

Aspergillus spp., Sporothrix schenckii, other Dematiaceae, Mucor spp., and other phycomycetes, with the exception of Entomophthorales, are less sensitive to the action of ketoconazole.

It is also active against staphylococci and streptococci.

Ketoconazole inhibits the biosynthesis of ergosterol in fungi, leading to changes in the composition of lipid components in the membranes.

It reduces androgen production.

Pharmacokinetics

Absorption – high (especially in the acidic environment of the stomach). Bioavailability is directly dependent on the size of the administered dose. The mean C_max of ketoconazole in plasma (3.5 µg/ml) is reached 1-2 hours after a single oral dose of 200 mg of the drug taken with food. Elimination from plasma is biphasic: during the first 10 hours T_1/2 is 2 hours, and subsequently – 8 hours. Plasma protein binding is 99%. It is well distributed in body tissues and fluids. It penetrates into the cerebrospinal fluid and testes in insignificant amounts (does not create therapeutic concentrations), crosses the placenta, and enters breast milk. It is metabolized in the liver into a large number of inactive metabolites. The main pathways of metabolism are oxidation and cleavage of the imidazole and piperazine rings, oxidative o-dealkylation, and aromatic hydroxylation. It is an inhibitor of the isoenzymes CYP2C19 and CYP3A4, CYP3A5, CYP3A7. It is excreted unchanged and as inactive metabolites: within 4 days, 70% of the administered dose is excreted (57% – with bile and 13% – by the kidneys). The pharmacokinetic characteristics of ketoconazole generally differ insignificantly in patients with hepatic or renal impairment and in patients without such impairment.

Indications

Infections of the smooth skin, scalp, caused by dermatophytes and/or yeast fungi in cases where local treatment is not applicable due to the large size of the affected areas, significant depth of the lesion, as well as in the absence of effect from previously conducted local treatment

• Dermatophytosis;
• Pityriasis versicolor;
• Folliculitis caused by fungi of the genus Pityrosporum;
• Chronic candidiasis of the skin and mucous membranes (including the oral cavity, pharynx, and esophagus);
• Chronic recurrent vaginal candidiasis in the absence of effect from local therapy.

Systemic fungal infections

• Paracoccidioidomycosis;
• Histoplasmosis;
• Coccidioidomycosis;
• Blastomycosis.

ICD codes

Dosage Regimen

Ointment

For dermatomycosis of smooth skin (tinea cruris, tinea manuum and pedis, cutaneous candidiasis, and pityriasis versicolor), the ointment is applied to the affected area and the area immediately adjacent to it once a day.

For seborrheic dermatitis, the ointment is applied to the affected area 1-2 times a day, depending on the severity of the lesion.

The average duration of treatment is: for dermatomycosis of smooth skin – 3-4 weeks, for tinea cruris – 2-4 weeks, for tinea pedis – 4-6 weeks, for infections caused by yeast-like fungi – 2-3 weeks, for pityriasis versicolor – 2-3 weeks, for seborrheic dermatitis – 2-4 weeks.

Treatment should be continued for at least several days after the symptoms of the disease have disappeared. If clinical improvement is not observed after 4 weeks of treatment, the diagnosis should be clarified.

Shampoo

For external use. Apply Mycosoral^® shampoo to the affected areas of the skin or scalp for 3-5 minutes, then rinse with water.

Treatment

• Various types of dandruff and seborrheic dermatitis of the scalp: 2 times a week for 3-4 weeks;
• Pityriasis versicolor: daily for 5 days, and if there is no effect, extend the course to 7 days.

Prevention

• Various types of dandruff and seborrheic dermatitis of the scalp: weekly or once every two weeks;
• Pityriasis versicolor: daily for 3-5 days (a single course) in the spring before the onset of summer.

Tablets

Mycosoral^® should be taken orally, to improve drug absorption – with meals.

Adults

1 tablet (200 mg) once a day. If improvement does not occur with the indicated dose, the dose should be increased to 2 tablets (400 mg) once a day.

Vaginal candidiasis – 2 tablets (400 mg) once a day.

Children over 3 years of age

• With body weight from 15 to 30 kg – 1/2 tablet (100 mg) once a day;
• With body weight over 30 kg – doses indicated for adults.

Average duration of treatment.

• Vaginal candidiasis – 7 days;
• Dermatophytosis – about 4 weeks;
• Pityriasis versicolor – 10 days;
• Chronic candidiasis of the skin and mucous membranes (including the oral cavity, pharynx, and esophagus) – 2-3 weeks;
• Fungal infections of the scalp – 1-2 months;
• Paracoccidioidomycosis, histoplasmosis, coccidioidomycosis, blastomycosis – the usual duration of treatment is 6 months.

Adverse Reactions

From the digestive system decreased appetite, nausea, vomiting, abdominal pain, diarrhea, toxic hepatitis (increased activity of “liver” transaminases or alkaline phosphatase, hypercreatininemia).

From the central nervous system headache, dizziness, drowsiness, paresthesia, reversible increased intracranial pressure.

From the sensory organs photophobia.

From the hematopoietic organs thrombocytopenia, leukopenia, hemolytic anemia.

Allergic reactions urticaria, skin rash, fever, very rarely – anaphylactic shock, anaphylactoid and anaphylactic reactions, angioedema.

From the genitourinary system decreased libido in men, oligospermia, impotence, menstrual irregularities.

Other alopecia, gynecomastia (reversible), temporary decrease in plasma testosterone concentration (normalizes in less than 24 hours after administration).

Contraindications

• Hypersensitivity to ketoconazole or other components of the drug;
• Acute or chronic liver diseases;
• Lactation period;
• Children under 3 years of age;
• Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Concomitant use with terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, bepridil, disopyramide, halofantrine, levacetylmethadol, domperidone, and sertindole; triazolam and midazolam for oral use; HMG-CoA reductase inhibitors metabolized via CYP3A4 (simvastatin, lovastatin); ergot alkaloids (dihydroergotamine, ergometrine/ergotamine, methylergometrine); nisoldipine, eplerenone, irinotecan, everolimus.

With caution: hepatic insufficiency, achlorhydria, hypochlorhydria, adrenal cortex and pituitary insufficiency, concomitant use of potentially hepatotoxic drugs, alcoholism, pregnancy, age over 50 years (women).

Use in Pregnancy and Lactation

Mycosoral^® should not be prescribed to pregnant women, except in cases where the intended benefit to the mother outweighs the potential risk to the fetus. Since Ketoconazole penetrates into breast milk, breastfeeding is recommended to be discontinued while taking the drug.

Use in Hepatic Impairment

Contraindicated in acute or chronic liver diseases.

With caution: hepatic insufficiency.

In women over 50 years of age, with a history of liver disease, with drug intolerance, taking hepatotoxic drugs, and also if the duration of treatment with the drug exceeds 2 weeks, it is necessary to monitor liver function before starting treatment, after 2 weeks of treatment, and then monthly, since in these categories of patients the risk of toxic effects of the drug on the liver increases.

Pediatric Use

Used in children from 3 years of age according to indications.

Geriatric Use

With caution: age over 50 years (women).

Special Precautions

Before starting treatment, it is necessary to assess liver function to exclude acute or chronic liver diseases; during treatment, it is necessary to frequently and regularly monitor liver function in all patients in order not to miss the first signs of hepatotoxicity. The total dose of ketoconazole received (per course of treatment) is a risk factor for severe hepatotoxicity.

In women over 50 years of age, with a history of liver disease, with drug intolerance, taking hepatotoxic drugs, and also if the duration of treatment with the drug exceeds 2 weeks, it is necessary to monitor liver function before starting treatment, after 2 weeks of treatment, and then monthly, since in these categories of patients the risk of toxic effects of the drug on the liver increases.

It is very important to inform patients who require long-term treatment with the drug about the symptoms of liver disease (increased fatigue, loss of strength, fever, dark urine, discolored stools, jaundice).

If symptoms of hepatitis appear or if liver function tests confirm liver disease, treatment should be stopped immediately. If treatment of skin lesions was carried out with glucocorticosteroids, then Ketoconazole is prescribed no earlier than 2 weeks after their discontinuation.

Patients taking antacid drugs (e.g., aluminum hydroxide) should take them no earlier than 2 hours after taking the drug.

In patients with achlorhydria or hypochlorhydria, due to an unpredictable decrease in the degree of absorption, Ketoconazole may be ineffective when taken orally. Consumption of acidic drinks increases the absorption of ketoconazole.

When used in a dose of 400 mg and more, a decrease in the “cortisol response” during adrenal stimulation with adrenocorticotropic hormone (ACTH) is observed, therefore, during treatment, it is necessary to monitor adrenal function in patients with adrenal insufficiency, as well as in patients undergoing significant stress (including extensive surgical interventions).

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Treatment gastric lavage, activated charcoal, symptomatic therapy, monitoring of the patient’s condition. There is no specific antidote.

Drug Interactions

Drugs that affect the metabolism of ketoconazole.

• Inducers of microsomal oxidation, such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine, and phenytoin significantly reduce the bioavailability of ketoconazole. The use of ketoconazole with such drugs is not recommended;
• Ritonavir increases the bioavailability of ketoconazole, therefore, when used together, the dose of ketoconazole should be reduced.

The effect of ketoconazole on the metabolism of other drugs.

Ketoconazole may enhance or prolong the effect of drugs metabolized with the participation of cytochrome P450, especially from the CYP3A group.

Cannot be prescribed during a course of treatment with ketoconazole:

• Terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, bepridil, disopyramide, halofantrine, levomethadyl, domperidone, and sertindole. The risk of severe ventricular tachycardia, including torsades de pointes, increases;
• Midazolam and triazolam (oral forms), HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme, such as simvastatin and lovastatin, ergot alkaloids (dihydroergotamine, ergometrine, ergotamine, methylergometrine), nisoldipine, eplerenone, irinotecan, everolimus. The effects, including side effects, of these drugs are enhanced.

Drugs for which it is necessary to monitor their plasma concentration, the severity of therapeutic effects and side effects (their dosage when used concomitantly with ketoconazole should be reduced if necessary):

• Oral anticoagulants;
• HIV protease inhibitors such as indinavir, saquinavir;
• Some anticancer drugs such as Vinca rosea alkaloids, busulfan, docetaxel, erlotinib, imatinib;
• Dihydropyridine “slow” calcium channel blockers metabolized by the CYP3A4 isoenzyme and possibly verapamil;
• Some immunosuppressive agents: cyclosporine, tacrolimus, sirolimus;
• Sildenafil, tolterodine;
• Some HMG-CoA reductase inhibitors, for example, atorvastatin;
• Some glucocorticosteroids such as budesonide, fluticasone, dexamethasone, and methylprednisolone;
• Other drugs: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, rifabutin, trimetrexate, ebastine, reboxetine, quetiapine, solifenacin, cilostazol, eletriptan, fentanyl, repaglinide.

Ethanol and other hepatotoxic drugs increase the risk of liver parenchymal damage. When used concomitantly with ethanol, disulfiram-like reactions may occur.

Weakens the effect of amphotericin B.

Reduces the stimulating effect of corticotropin on the adrenal glands.

Increases the risk of breakthrough bleeding with simultaneous use of low-hormone oral contraceptives.

Enhances the toxicity of phenytoin.

Antacid and anticholinergic drugs, H2-histamine receptor blockers, and other drugs that reduce gastric acidity reduce the absorption of ketoconazole.

Storage Conditions

Store the drug in a place inaccessible to children, dry and protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.