Oronazole - instructions for use, dose, side effects, contraindications

Similar drugsTo uncover

Dosage form: & nbsppills

Composition:

1 tablet contains:

active substance: ketoconazole 200 mg;

Excipients: corn starch, lactose monohydrate, povidone, microcrystalline cellulose, silicon dioxide colloid, anhydrous, magnesium stearate.

Description:

Round tablets with bevelled edges and a notch on one side, from white to light gray.

Pharmacotherapeutic group:Antifungal agent

Pharmacodynamics:

Ketoconazole is a synthetic derivative of imidazolidioxole that has a fungicidal or mycostatic effect against dermatophytes, yeasts (Candida, Pityrosporum, Torulopsis, Cryptococcus), dimorphic fungi and higher fungi (eumycetes). Less sensitive to the action of ketoconazole: Aspergillus spp., Sporothrix schenckii, some Dermatiaceae, Mucor spp. and other fikomitsety, except for Enomophthorales.

Ketoconazole inhibits the biosynthesis of ergosterol in fungi, which leads to a change in composition of the lipid components in the membranes.

At a therapeutic dose of 200 mg per day, there may be a transient decrease in the concentration of testosterone in the plasma. The testosterone concentration returns to the baseline within 24 hours after the administration of ketoconazole. During prolonged therapy with this dosage, testosterone concentration usually differs slightly from control.

Ketoconazole in a daily dose of 400 mg or more did not cause a decrease in the cortisol response to stimulation of ACTH in volunteers.

Pharmacokinetics:

The maximum concentration of ketoconazole in plasma is 3.5 mg / ml achieved 1-2 hours after a single oral intake of 200 mg of the drug during meals.

In vitro binding to plasma proteins, mainly with the albumin fraction, is 99%. Only a small part of the drug penetrates into the cerebrospinal fluid. Ketoconazole is a weak dibasic substance, which needs an acidic medium for dissolution and absorption.

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

The main ways of metabolism are the oxidation and cleavage of imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. Ketoconazole It is not an inductor of its own metabolism.

About 13% of the dose is excreted through the kidneys, of which 2 to 4% is unchanged drug. The drug is excreted mainly with bile in the gastrointestinal tract.

The excretion from the plasma is two-phase: T_1/2 = 2 hours during the first 10 hours, and subsequently - 8 hours.

The pharmacokinetic characteristics of ketoconazole generally differ slightly in healthy individuals and in patients with hepatic or renal insufficiency.

Indications:

Smooth skin infections of the 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 lesion depth, and also in the absence of the effect of previous local treatment:

- dermatophytosis;

- colored lichen;

folliculitis caused by fungi of the genus Pityrosporum;

Candidiasis of the esophagus;

Candidiasis of the mouth and pharynx;

- chronic candidiasis of skin and mucous membranes;

- chronic recurrent candidiasis of the vagina in the absence of the effect of local therapy.

Systemic fungal infections:

- Paracoccidioidosis;

- Histoplasmosis;

- coccidioidosis;

- blastomycosis.

Prophylactic use in patients with reduced protective forces of the body (congenital or caused by the disease or action of drugs), as in these cases the risk of fungal infections increases.

The use of ketoconazole in fungal meningitis is not advisable, since the drug penetrates poorly through the BBB.

Contraindications:

- Hypersensitivity to ketoconazole or excipients;

- children under 3 years (for this dosage form) and body weight up to 15 kg (efficacy and safety not studied);

- acute or chronic liver disease;

- simultaneous administration with ketoconazole: substrates CYP3A4: astemizole, terfenadine, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmetadol, misolastine, pimozide, quinidine or sertindole, t. an increase in the concentration of these drugs in plasma can lead to an extension of the QT interval on the ECG and the development of ventricular arrhythmias of the "torsade de pointe" type; domperidone, tk. an extension of the QT interval is possible; triazolam and midazolam for oral administration; inhibitors of HMG-CoAGreductase, metabolized by CYP3A4, such as simvastatin and lovastatin; ergot alkaloids, for example, dihydroergotamine, ergometrine, ergotamine, methylergometrine (methylergonovine); nisoldipine; eplerenone; irinoteverolimus. (see also section "Interaction with other drugs");

- hereditary intolerance to galactose, deficiency of Lapp's lactase or impaired absorption of glucose-galactose.

Carefully:

- Simultaneous reception of drugs that reduce the acidity of gastric juice (antacids, blockers H₂-histamine receptors, proton pump inhibitors);

- women over 50 years old, liver disease in history, drug intolerance, the use of hepatotoxic drugs, duration of treatment with Oronazole for more than 2 weeks;

- Insufficiency of adrenal function;

- Patients undergoing significant stress (extensive surgical interventions, resuscitation, etc.);

- porphyria.

Pregnancy and lactation:

At the moment, there is limited information on the use of ketoconazole during pregnancy. In animal studies, reproductive toxicity of ketoconazole was found. The degree of potential risk to a person is unknown. Therefore, Oronazole tablets should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus.

Because the ketoconazole penetrates into breast milk, breastfeeding when taking Oronazole is not recommended.

Dosing and Administration:

Inside, with food to improve absorption.

Therapeutic application

Adults: one tablet (200 mg) once a day with meals. If there is no improvement in taking this dose, the dose should be doubled (400 mg once a day).

Vaginal candidiasis: two tablets (400 mg) once a day with meals.

Children over 3 years old:

- with a body weight of 15 to 30 kg: 1/2 tablet (100 mg) once a day;

- with a body weight of more than 30 kg: the doses indicated for adults.

Average duration of treatment:

- vaginal candidiasis - 7 days;

- skin mycoses caused by dermatophytes - about 4 weeks;

- multi-colored lichen -10 days;

- Candidiasis of the skin and oral cavity - 2-3 weeks;

- fungal lesions of the scalp -1-2 months;

- Paracoccidioidomycosis, histoplasmosis, coccidiodomycosis - usually the duration of treatment is 6 months.

For all indications, treatment should be continuous until clinical parameters and laboratory indicators indicate eradication of the pathogen.

Side effects:

Classification of the incidence of adverse events (WHO): very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10 000, <1/1000); very rarely (<1/10 000), including individual messages.

From the side of the blood and lymphatic system: very rarely - thrombocytopenia.

From the immune system: very rarely - allergic reactions, including anaphylactic shock, anaphylactoid and anaphylactic reactions, angioedema.

From the endocrine system: very rarely - adrenal insufficiency.

From the central nervous system: very rarely - a reversible increase in intracranial pressure (for example, edema of the optic discs, vomiting "fountain" in children, swelling of the fontanelle in young children), dizziness, headache, paresthesia.

From the side of the organ of vision: very rarely - photophobia.

From the gastrointestinal tract: very rarely - vomiting, abdominal pain, diarrhea, dyspepsia, nausea.

From the liver and bile ducts: very rarely - severe hepatotoxicity, including jaundice, hepatitis, hepatonecrosis (confirmed by biopsy), liver cirrhosis, hepatic insufficiency (including cases of liver transplantation and death) (see section "Special instructions"), violation of laboratory parameters of liver function .

From the skin and subcutaneous fat: very rarely - hives, itching, rashes, alopecia.

From the genitals and mammary glands: very rarely - azoospermia at doses exceeding therapeutic 200 or 400 mg per day, erectile dysfunction, gynecomastia (reversible), menstrual cycle disorders.

Overdose:

Symptoms: nausea, vomiting, dizziness and headache, paresthesia and seizures.

Treatment: in case of an overdose within the first hour after taking the drug, it is necessary to cancel the drug, to wash the stomach, to prescribe Activated carbon. Necessary: monitoring the patient's condition and performing symptomatic treatment.

Interaction:

1. Drugs that reduce the acidity of gastric juice (antacids, blockers H₂-histamine receptors, proton pump inhibitors), reduce ketoconazole absorption. Therefore, the use of these drugs is recommended at least 2 hours before or 2 hours after taking ketoconazole.

2. Drugs that affect the metabolism of ketoconazole:

A) significantly reducing the bioavailability of ketoconazole: induction preparations of microsomal oxidation, such as rifampicin, rifabutin, carbamazepine, nevirapine, phenytoin and isoniazid. The use of ketoconazole simultaneously with such drugs is not recommended;

B) increasing the bioavailability of ketoconazole, such as ritonavir (as a result, with simultaneous admission, it is necessary to reduce the dose of ketoconazole).

3. Effect of ketoconazole on the metabolism of other drugs:

A) ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A: astemizole, terfenadine, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmetadol, misolastine, pimozide, quinidine or sertindole, domperidone. As a result, the concentrations of these drugs increase, which leads to an increase in the frequency and / or duration of effects, including side effects (for example, the duration of the QT interval on the ECG is the risk of ventricular tachycardia of the "torsade de pointe" type. concomitantly with ketoconazole.

B) a similar interaction with HMG-CoA reductase inhibitors metabolized by CYP3A4, such as, simvastatin and lovastatin. Do not use these drugs at the same time as ketoconazole.

B) possible interactions with ergot alkaloids, for example, dihydroergotamine, ergometrine, ergotamine, methylergometrin (methylergonovine); nisoldipine; eplerenone. Do not use these drugs at the same time as ketoconazole.

Also, interactions with triazolam and midazolam (prolongation of the sedative effect of midazolam) are possible. Therefore, one should not simultaneously apply ketoconazole with midazolam in the dosage form for oral administration, while intravenous administration of midazolam is allowed only with adequate monitoring of the patient's condition.

4. Preparations, in the appointment of which it is necessary to monitor their concentration in the blood plasma, the severity of the therapeutic effects and side effects. Their dosage when taken concomitantly with ketoconazole should be reduced if necessary:

- some immunosuppressants: ciclosporin, tacrolimus, sirolimus;

- anticoagulants;

- Some glucocorticosteroids, such as budesonide, dexamethasone and methylprednisolone;

- HIV protease inhibitors, such as indinavir, saquinavir;

- Some antineoplastic agents, such as vinca alkaloids pink, busulfan and docetaxel;

- metabolized with the help of the isoenzyme CYP3A4 blockers "slow calcium channels" dihydropyridine series and, possibly, verapamil.

- some inhibitors of HMG-CoA reductase, for example, atorvastatin;

- other drugs: digoxin, buspirone, alfentanil, alprazolam, brothisolam, trimetrexate, ebastine, reboxetine, cilostazol, eletriptan, fentanyl, repaglinide, sildenafil, tolterodine.

In isolated cases with simultaneous reception with alcohol, there were disulfiram-like reactions characterized by reddening of the skin, rash, peripheral edema, nausea and headache. These symptoms passed independently for several hours.

Special instructions:

When taking Oronazole tablets, there is a risk of developing serious hepatotoxic effects. Therefore, Oronazole should be used in the following cases: when the potential benefit exceeds the possible risk, if the local dosage forms of ketoconazole are ineffective, with resistance to fluconazole, terbinafine or itraconazole or their intolerance.

Hepatotoxicity. In women older than 50 years, with liver disease in history, with drug intolerance, the simultaneous use of hepatotoxic drugs, the risk of toxic effects of the drug on the liver increases. If severe weakness develops with fever, dermal itching, darkening of the urine, and discoloration of the stool, jaundice and abdominal pain, stop taking the medication immediately, consult a doctor and assess liver function.

Control of liver function. When the duration of therapy with ketoconazole is more than 2 weeks, it is necessary to conduct a study of liver function before the start of therapy, after 2 and 4 weeks of therapy and then monthly. If any of the indicators of liver function increases to values three times higher than the upper limit of the norm, the use of ketoconazole should be discontinued.

Control of adrenal function.In patients with adrenal insufficiency, as well as in patients undergoing prolonged and significant stressful effects (extensive surgical interventions, resuscitation, etc.), when administering the drug, adrenal function should be monitored, ketoconazole reduces the response of cortisol to stimulation with adrenocorticotropic hormone (ACTT).

In vitro studies ketoconazole It is considered unsafe in patients with porphyria, so if possible, ketoconazole should be avoided in porphyria.

Data on the use of the drug Oronazole in children weighing less than 15 kg are very limited. Therefore, this category of patients should not be prescribed.

Oronazole contains lactose, so patients with hereditary intolerance to galactose, a deficiency of Lapp's lactase or glucose-galactose malabsorption syndrome should not take the drug.

Effect on the ability to drive transp. cf. and fur:

Has no influence.

Form release / dosage:

Tablets of 200 mg.

Packaging:

For 20 tablets in a bottle of dark glass with an aluminum lid with the control of the first autopsy. Free space in the vial is filled with cotton absorbent cotton.

1 bottle in a cardboard pack together with instructions for use.

Storage conditions:

Store in a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013691 / 01

Date of registration:25.03.2008

Expiration Date:Unlimited

Date of cancellation:2015-05-08

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp12.06.2017

Illustrated instructions

Instructions

Oronazole (Oronazol)