Universal reference book for medicines

Active substance: ketoconazole

Type: Antifungal medication

Manufacturer: KRKA (Slovenia)
Description of the active substance:
This information is a reference and it is not enough that the drug has been prescribed by a doctor ..

Antifungal agent.
It has a fungicidal and fungistatic effect. The mechanism of action consists in inhibiting the synthesis of ergosterol and changing the lipid composition of the membrane. It is active against the pathogen of multi-colored lichen Malassezia furfur, the causative agents of some dermatomycoses (Trichophyton, Epidermophyton floccosum, Microsporum), candida pathogens (Candida), and pathogens of systemic mycoses (Cryptococcus).
It is also active against gram-positive cocci: Staphylococcus spp., Streptococcus spp.

Ketoconazole is a weak dibasic compound that dissolves and is absorbed in an acidic medium.
C max of ketoconazole in plasma is about 3.5 μg / ml and is achieved 1-2 hours after a single oral intake at a dose of 200 mg during meals. Bioavailability of ketoconazole is maximal when taken with food. Absorption of ketoconazole is reduced in patients with low acidity of gastric juice, for example, taking antacid preparations 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 particular disease.
The binding to plasma proteins, mainly with 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 with the formation of a large number of inactive metabolites.

In vitro studies have shown that the isoenzyme CYP3A4 is involved in the metabolism of ketoconazole.
The main ways of metabolism are oxidation and cleavage of imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. Ketoconazole is not an inducer of its own metabolism. The elimination from the plasma is biphasic: during the first 10 hours, T 1/2 is 2 hours, followed by 8 hours.
About 13% is excreted in urine, of which 2-4% is unchanged.
It is allocated mainly with bile in the digestive tract and about 57% is excreted with feces.
For external use: treatment and prevention of fungal skin lesions of the scalp;
smooth skin dermatomycosis; inguinal epidermophytia; epidermophytosis of hands and feet, candidiasis of the skin.
For topical application: treatment of acute and chronic recurrent vaginal candidiasis;
prevention of fungal infections of the vagina with reduced resistance of the body and against treatment with antibacterial agents and other drugs that disrupt the normal vaginal microflora.
For oral administration (with inaccessibility and intolerance to other therapies): blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis.

For admission to adults and children with a body weight of more than 30 kg - 200-400 mg / day.
Children with body weight less than 30 kg - 4-8 mg / kg / day. Take 1 time / sut with meals.
For external and local administration, the dosing regimen depends on the indications and the dosage form used.

From the side of the nervous system: headache, dizziness, paresthesia, drowsiness, increased excitability, insomnia, anxiety, fatigue, general weakness, reversible increase in intracranial pressure (eg, edema of the optic discs, fontanelle swelling in young children).

On the part of the digestive system: nausea, abdominal pain, diarrhea, impaired liver function, vomiting, indigestion, constipation, dry mouth, dysgeusia, bloating, discoloration of the tongue, toxic hepatitis (increased hepatic transaminase or alkaline phosphatase, jaundice, severe hepatotoxicity , including cholestatic hepatitis, hepatonecrosis (biopsy), liver cirrhosis, liver failure (including cases of transplantation and death).

On the part of metabolism: alcohol intolerance, anorexia, hyperlipidemia, increased appetite.

On the side of the musculoskeletal system: myalgia, arthralgia.

From the respiratory system: nosebleeds.

From the skin and subcutaneous fat: alopecia, dermatitis, erythema, erythema multiforme, pruritus, rash, xeroderma, hot flushes, acute generalized exanthematous pustulosis, photosensitization.

From the cardiovascular system: orthostatic hypotension.

On the part of the endocrine system: gynecomastia, insufficiency of adrenal function, menstrual irregularity, it is possible a temporary decrease in the concentration of testosterone in the blood plasma (normalized 24 hours after admission).

From the senses: photophobia.

Allergic reactions: rash, hives, anaphylactic shock, anaphylactic reactions, angioedema.

On the side of the immune system: pseudo-anaphylactic shock.

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

On the part of laboratory indicators: a decrease in the number of thrombocytopenia.

Common reactions: fever, peripheral edema, chills.

Acute and chronic liver diseases, pregnancy, lactation, children under 3 years of age, hypersensitivity to ketoconazole;
simultaneous administration with the following substrates of the isoenzyme CYP3A4 (an increase in the concentration of these drugs in plasma caused by a joint intake with ketoconazole may lead to an increase or prolongation of both the therapeutic and side effects and the development of potentially dangerous effects, including the prolongation of the QT interval and development of ventricular arrhythmia such as "pirouette"): analgesics (levacetylmetadol, methadone); antiarrhythmics (disopyramide, dofetilide, dronedarone, quinidine); anthelmintic and antiprotozoal drugs (halofantrine); antihistamines (astemizole, misolastine, terfenadine); preparations for the treatment of migraine (dihydroergotamine, ergometrine, ergotamine, methylergometrine); antitumor drugs (irinotecan); antipsychotic drugs, anxiolytics and hypnotics (lurasidone, midazolam orally, pimozide, sertindole, triazolam); calcium channel blockers (beprideal, felodipine, lercanidipine, nisoldipine); cardiovascular drugs of different groups (ivabradine, ranolazine); diuretics (eplerenone); immunosuppressants (everolimus); gastrointestinal drugs (cisapride, domperidone); lipid-lowering drugs (lovastatin, simvastatin); other (colchicine in the treatment of patients with impaired liver and kidney function).
Contraindicated in pregnancy and lactation (breastfeeding).

Contraindicated in severe impairment of kidney function.

Contraindicated in severe violations of liver function.

Use in fungal meningitis is impractical, because
ketoconazole poorly penetrates the BBB.
Because of the risk of hepatotoxicity, incl.
Ketoconazole should be used only in cases where the potential benefit
exceeds the possible risk.

In patients with increased hepatic enzyme activity or with transferred toxic liver damage due to the use of other drugs, ketoconazole should not be used, unless the expected benefit justifies the risk of liver damage.

Before the beginning of treatment it is necessary to evaluate the function of the liver in order to avoid acute or chronic diseases.
During treatment it is necessary to regularly monitor the picture of peripheral blood, the functional state of the liver and
kidneys in patients in order to not miss the first symptoms of hepatotoxicity.
It is impossible to exclude the development of hepatotoxicity during the first month, and even during the first week of therapy. The total dose of ketoconazole is a risk factor for severe hepatotoxicity. Therefore, during the treatment period it is recommended to regularly monitor liver function in patients receiving ketoconazole therapy.
In patients with adrenal insufficiency or borderline conditions against a background of stressful effects (including extensive surgical interventions, intensive care conditions), in patients with a prolonged course of therapy, if adrenal insufficiency is suspected, adrenal function should be monitored.
in volunteers, ketoconazole at a daily dose of 400 mg or more caused a decrease in the "cortisol response" to stimulation of ACTH.
If SCS was used to treat skin diseases , then ketoconazole is prescribed no earlier than 2 weeks after their withdrawal.

The use of acidic drinks increases the absorption of ketoconazole.

With the simultaneous use of ketoconazole with antacid agents (aluminum hydroxide, histamine H2 blockers, proton pump inhibitors), absorption of ketoconazole from the digestive tract decreases.
With these combinations, the antifungal activity of ketoconazole should be monitored and, if necessary, corrected for its dose.
With the simultaneous use of ketoconazole with powerful inducers of the CYP3A4 isoenzyme, a decrease in the bioavailability of ketoconazole is possible, which may cause a significant decrease in its effectiveness.
These drugs include isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine. If these combinations can not be avoided, then the antifungal activity of ketoconazole should be monitored and, if necessary, increased its dose.
With the 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 should be monitored to detect symptoms of increased intensity and duration of action of ketoconazole, the concentration of ketoconazole in the blood plasma and, if necessary, reduce its dose.
With simultaneous use, ketoconazole is able to inhibit CYP3A4-mediated drug metabolism, as well as transport of active substances due to P-glycoprotein.
This can lead to an increase in the concentrations of these drugs in plasma and / or from active metabolites, which causes an increase in the intensity and duration of the therapeutic or side effects of concomitant medications.
It is not recommended to use the following drugs with ketoconazole simultaneously: tamsulosin, fentanyl, rifabutin, rivaroxaban, carbamazepine, dasatinib, nilotinib, trabectidine, salmeterol.
If these combinations can not be avoided, clinical monitoring of the patient's condition should be provided to detect symptoms of an increase in intensity or duration of therapeutic and / or side effects, monitor the concentration of the drug in the blood plasma and, if necessary, reduce the dose of the drug or suspend its use.
Caution is advisable to use ketoconazole simultaneously with the following drugs: alfentanil, buprenorphine (iv and sublingual), oxycodone, digoxin, coumarins, cilostazol, repaglinide, saxagliptin, praziquantel, ebastin, eletriptan, bortezomib, busulfan, docetaxel, erlotinib, imatinib, Ixabepilone , lapatinib, trimetrexate, vinca alkaloids, alprazolam, aripiprazole, brotisolam, buspirone, haloperidol, midazolam (iv), perosporone, quetiapine, ramelteron, risperidone, maraviroc, indinavir, saquinavir, nadolol, verapamil, aliskiren, apipi
ant, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, sirolimus, tacrolimus, temsirolimus, atorvastatin, reboxetine, fesoterodine, imidafenatsin, sildenafil, solifenacin, tadalfil, tolterodine, alitretinoin (oral dosage form), cinacalcet, mozavaptan, tolvaptan. When combined, careful monitoring of the clinical condition of the patient is recommended, if necessary - monitoring the concentration of the drug in the blood plasma and, if necessary, reducing its dose.
In isolated cases, a disulfiram-like reaction is possible when alcohol is consumed during the administration of ketoconazole.

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