Itraconazole, 100 mg capsules 14 pcs
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Pharmacotherapeutic group:antifungal agent.
ATH code: J02AC02
Pharmacokinetics
Due to non-linear pharmacokinetics, itraconazole accumulates in blood plasma when taken repeatedly. The equilibrium concentration (Css) of itraconazole is usually reached within about 15 days, while the maximum concentration (Cmax) and AUC (area under the curve “concentration-time”) values of itraconazole during multiple administration are 4-7 times higher than when administered single time. Maximum equilibrium plasma concentration (Cssmax) of itraconazole is about 2 mcg/ml when administered 200 mg itraconazole once daily. Final elimination half-life (T1/2) usually is 16-28 hours in single dose and 34-42 hours in multiple dose. Concentration of itraconazole in plasma decreases to almost undetectable value during 7-14 days after discontinuation of therapy, depending on the dose prescribed and the duration of treatment. Clearance of itraconazole decreases at higher doses due to saturation of its metabolization pathways in the liver.
Absorption
Itraconazole is rapidly absorbed after oral administration. Cssmax of unchanged itraconazole in plasma is reached within 2-5 hours after oral administration. Absolute bioavailability (F) of itraconazole after oral administration is about 55%. During oral administration maximum F of itraconazole is observed when taking capsules immediately after a meal.
Absorption of itraconazole in capsules is decreased in patients with low acidity of gastric juice, for example, during usage of medicines suppressing secretion of hydrochloric acid in stomach (such as H2-histamine ‑receptor antagonists‑, proton pump inhibitors), or in patients with achlorhydria during different diseases. Absorption of itraconazole on an empty stomach in such patients is increased when taking the drug simultaneously with acidic beverages (such as non-diet coke). Absorption of itraconazole remains unchanged at a dose of 200 mg once daily on an empty stomach together with non-dietic cola after prior use of H2-histamine ‑receptor ‑antagonist ‑ranitidine.
Exposure to itraconazole is lower when taking itraconazole as a capsule compared with exposure to itraconazole.
Distribution
Itraconazole binds 99.8% to plasma proteins, mainly to albumin (hydroxyitraconazole binds to albumin by 99.6%). Affinity to lipids is also noted. Only 0.2% of itraconazole remains unbound in plasma. Apparent volume of distribution (Vd) >700 l, indicating its significant distribution in tissues. Concentrations in the lungs, kidneys, bones, stomach, spleen and muscles, are 2-3 times higher than the corresponding concentrations in plasma, while the drug concentration in tissues containing keratin, especially in the skin, is about 4 times higher than the concentration in plasma. Concentration in cerebrospinal fluid is significantly lower than in plasma, however, the effectiveness of itraconazole against infectious agents present in cerebrospinal fluid has been demonstrated.
Metabolism
As shown in in vitro studies, CYP3A4 is the main isoenzyme involved in the metabolism of itraconazole. Itraconazole undergoes active metabolism in the liver with the formation of numerous metabolites. The main metabolite is hydroxyitraconazole, which in vitro has antifungal activity comparable with itraconazole. Concentrations of hydroxyitraconazole in plasma are about 2 times higher than concentrations of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites with urine (35%) and feces (54%) for 1 week after oral solution administration. Renal excretion of itraconazole and its active metabolite hydroxyitraconazole is less than 1% of the dose of the drug administered intravenously. On the basis of results of studying pharmacokinetics of 14Cmethylated ‑drug after oral administration the excretion of unchanged itraconazole with feces varies from 3% to 18% of the dose taken.
As redistribution of itraconazole from tissues containing keratin is insignificant, excretion of itraconazole from these tissues is associated with regeneration of epidermis. In ‑contrast to blood plasma, the concentration of itraconazole in the skin is maintained for 2 to 4 weeks after stopping the 4-week ‑treatment, and the concentration in the nail keratin, where itraconazole can be detected as early as 1 week after starting treatment, is maintained for at least 6 months after the end of the 3-month ‑course of treatment.‑
Special patient categories
. Impaired liver function
Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study compared the pharmacokinetic parameters of patients with cirrhosis and healthy volunteers. In patients with cirrhosis, the mean plasma Cmax was significantly lower (by 47%) than in healthy volunteers when a single dose of 100 mg of itraconazole was administered. The mean T1/2 on a single dose was increased in patients with cirrhosis and was 37 ± 17 hours compared to 16 ± 5 hours for healthy volunteers. Mean exposure of itraconazole (AUC) was similar in patients with cirrhosis and in healthy volunteers. There are no data on long-term use of itraconazole in patients with cirrhosis (see sections “Dosage and administration” and “Cautions”).
Renal dysfunction.
There are limited data on oral use of itraconazole in patients with renal dysfunction. In patients with uremia who had a mean creatinine clearance (CK) of 13 mL/min × 1.73 m2, the systemic exposure (AUC) of itraconazole was slightly lower compared to the main population. There was no significant effect of hemodialysis or long-term outpatient peritoneal dialysis on itraconazole pharmacokinetics (Tmax, Cmax and AUC0-8 h).
After a single intravenous administration of the drug, the final T1/2 of itraconazole in patients with mild (defined in the study as CK 50-79 ml/min), moderate (CK 20-49 ml/min) or severe renal impairment (CK < 20 ml/min) similar to that in healthy subjects (range of mean values 42-49 hours compared to 48 hours in patients with impaired renal function and healthy volunteers, respectively). Total exposure to itraconazole, based on the AUC score, was reduced in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, compared to patients with no renal impairment.
Data on long-term use of itraconazole in patients with renal impairment are not available. Dialysis has no effect on the T1/2 or clearance of itraconazole or hydroxyitraconazole.
Children
Data on the pharmacokinetics of itraconazole in pediatric patients are limited. Clinical studies of pharmacokinetics in children and adolescents aged 5 months to 17 years were conducted using itraconazole in capsules, oral solution, and intravenous solution. Individual doses of the drug in capsule form and oral solution ranged from 1.5 to 12.5 mg/kg/day when taken once or twice daily. When receiving itraconazole in the same daily dose twice a day compared to once daily administration, Cmax and Cmin were comparable to those in adult patients when taking itraconazole once a day. There were no significant age-related differences in AUC and total clearance of itraconazole; in rare cases a slight correlation between the age of patients and values of Vd of the drug, Cmax and final T1/2 was observed. The established clearance of itraconazole and its Vd depend on the body weight of patients.
Pharmacodynamics
Itraconazole is a synthetic antifungal agent of broad spectrum action, a triazole derivative. Mechanism of action of itraconazole is inhibition of ergosterol biosynthesis – the main component of the cell membrane of fungus, involved in maintaining the structural integrity of the membrane. Violation of ergosterol synthesis leads to changes in membrane permeability and cell lysis, which determines antifungal effect of the drug.
Itraconazole is active against infections caused by fungi:
– dermatophytes (Trichophyton spp, Microsporum spp., Epidermophyton floccosum);
– yeast-like fungi (Candida spp, including C. albicans, C. tropicalis, C. parapsilosis, C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp, including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides immitis, Pseudallescheria boydii; Penicillium marneffei and many others.
Candida krusei, Candida glabrata and Candida tropicalis are the least sensitive Candida species to the action of itraconazole.
The main types of fungi whose development is not inhibited by itraconazole are Zygomyces (Rhizopus spp, Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Resistance to azoles develops slowly and is often the result of several genetic mutations. Described mechanisms for the development of resistance include overexpression of the ERG11 gene encoding the 14α-demethylase enzyme, which is the primary target of azole action, and point mutations in ERG11 that result in reduced enzyme binding to azoles and/or activation of transport systems, resulting in increased azole excretion. Cross-resistance of Candida spp. to azole group drugs has been observed, although resistance to one drug of this group does not necessarily mean resistance to other drugs of the azole group. Aspergillus fumigatus strains resistant to itraconazole have been reported.
Indications
Skin lesions and mucous membranes: vulvovaginal candidiasis; dermatomycosis; pityriasis; oral candidiasis; fungal keratitis.
– Onychomycosis caused by dermatophytes and/or yeast-like fungi.
– Systemic mycoses: systemic aspergillosis and candidiasis; cryptococcosis (including cryptococcal meningitis): in immunodeficient patients and in all patients with central nervous system cryptococcosis, itraconazole should be prescribed only if first-line drugs are not applicable in the case or are not effective; histoplasmosis; sporotrichosis; paracoccidioidomycosis; blastomycosis; other rare systemic or tropical mycoses.
Active ingredient
Itraconazole
Composition
Each capsule contains itraconazole pellets (22%) – 0.460 g.
Content of the pellets:
The active ingredient: itraconazole – 0.100 g;
Auxiliary substances: Hypromellose (hydroxypropyl methylcellulose E-5) – 0.1472 g, butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1:2:1] (Eudragit E-100) – 0.0046 g, sucrose (sugar) – 0.2070 g.
Composition of the capsule shell:
casing: gelatin, titanium dioxide (E 171), azorubin (carmoisine) E 122;
caps: gelatin, titanium dioxide (E 171), indigo carmine – F D&C Blue 2 (E 132).
How to take, the dosage
Itraconazole should be taken immediately after eating for optimal absorption. The capsules should be swallowed whole.
Indication | Dose | Treatment duration < | ||||||||||||||||
Vulvovaginal candidiasis | 200 mg 2 times daily or 200 mg once daily | 1 day or 3 days | Lingonitis < | 200 mg once daily | 7 days | |||||||||||||
Dermatomycoses of smooth skin | 200 mg once daily or 100 mg once daily | 7 days or 15 days | ||||||||||||||||
Lesions of highly keratinized areas of the skin, such as the hands and feet | 200 mg 2 times daily or 100 mg once daily | 7 days or 30 days | ||||||||||||||||
Oral mucosal candidiasis | 100 mg once a day | 100 mg once a day/p> | 15 days | |||||||||||||||
Bioavailability of itraconazole when taken orally may be reduced in some patients with compromised immunity, such as those with neutropenia, AIDS patients, or organ transplants. Consequently, doubling the dose may be necessary. | ||||||||||||||||||
Fungal keratitis | 200 mg once daily | 21 days Duration of treatment may be adjusted depending on improvement in clinical picture | ||||||||||||||||
Onychomycoses caused by dermatophytes and/or yeast-like and mold fungi | Onychomycoses caused by dermatophytes and/or yeast-like and mold fungi | |||||||||||||||||
Onychomycoses – pulse therapy | Doses and duration of treatment | |||||||||||||||||
One course of pulse therapy consists of taking 2 capsules of Itraconazole twice daily (200 mg twice daily) for 1 week. For the treatment of fungal lesions of nail plates of hands 2 courses are recommended. For the treatment of fungal lesions of the nail plates of the feet it is recommended 3 courses. Interval between courses, during which it is not necessary to take the drug, is 3 weeks. Clinical results will be evident after the end of treatment, as the nails grow back. | ||||||||||||||||||
Localization of onychomycosis | 1st week. | 2nd week. | 3rd week. | 4th week. | 5th week. | 6th week. | 7th week. | 8th week. | 9th week. | |||||||||
Foot toe nail plate lesions with or without hand toe nail plate lesions | 1st course | Weeks free from taking Itraconazole /p> | 2nd course | Weeks free from taking Itraconazole | 3rd course | |||||||||||||
Defections of the nail plates of the hands | 1st course | Weeks free from taking Itraconazole /p> | 2nd course | /td> | ||||||||||||||
Onychomycosis – continuous treatment |
Duration of treatment | |||||||||||||||||
Foot nail plate lesions with or without hand nail plate lesions | 200 mg per day /p> | 3 months | ||||||||||||||||
Excretion of Itraconazole from the skin and nail tissue is slower than from the plasma. Thus, optimal clinical and mycological effects are achieved 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of treatment for nail infections.
Systemic mycoses | |||||
Indication | Dose | Average duration of treatment* | Remarks | ||
Aspergillosis | 200 mg once daily | 2-5 months | Increase the dose to 200 mg 2 times daily in case of invasive or disseminated disease | ||
Candida |
3 weeks to 7 months | Increase the dose to 200 mg 2 times a day in the case of invasive or disseminated disease | |||
Cryptococcosis (except meningitis) | 200 mg once daily | from 2 months to 1 year /td> | |||
Cryptococcal meningitis | 200 mg 2 times daily | 2 months to 1 year | Maintenance therapy – see Special Indications | ||
Histoplasmosis | from 200 mg once daily to 200 mg twice daily | 8 months | |||
Blastomycosis | 100 mg once daily to 200 mg twice daily | 6 months | |||
| 100 mg once daily | 3 months | |||
Paracoccidioidomycosis | 100 mg once daily | 6 months | td> There is no data on the efficacy of this dose for the treatment of paracoccidioidomycosis in AIDS patients | ||
Chromomycosis | 100-200 mg once daily /td> | 6 months |
* – the duration of treatment may be adjusted depending on the effectiveness of the treatment.
Special patient groups
Children There are limited data on the use of Itraconazole in children. The use of Itraconazole in children is not recommended unless the expected benefits of treatment outweigh the potential risks.
Elderly patients. The data on the use of Itraconazole for the treatment of elderly patients are limited. It is recommended to use itraconazole preparation for treatment of patients in this category only if the expected benefits of treatment exceed the potential risks. When choosing the dose of the drug for treatment of elderly patients it is recommended to take into account the decrease of liver, kidney and heart function, which are more frequent in elderly patients, as well as the presence of concomitant diseases or taking other medications.
Hepatic disorders. The data on the use of oral itraconazole for the treatment of patients with hepatic impairment are limited. Caution should be exercised when prescribing the drug in this category of patients.
Renal dysfunction. The data on the use of oral itraconazole for the treatment of patients with impaired renal function are limited. In some patients with renal impairment, the exposure of itraconazole may be reduced. The drug should be administered with caution in this category of patients, in some cases it may be necessary to change the dose of the medicinal product.
.
Interaction
Itraconazole is primarily metabolized by CYP3A4 isoenzyme. Other drugs that are also metabolized with participation of this isoenzyme or change its activity can affect the pharmacokinetics of itraconazole. Similarly, itraconazole may affect the pharmacokinetics of drugs that are also metabolized with the participation of this isoenzyme. Itraconazole is a strong inhibitor of CYP3A4 isoenzyme and P-glycoprotein. If itraconazole is used together with other medicinal agents, it is recommended to read the instructions for use to clarify the way of metabolism of the drug and to decide if it is necessary to change the dose.
Drugs that may decrease plasma concentrations of itraconazole
Drugs that may decrease plasma concentrations of itraconazole Medicinal products which reduce the acidity of gastric juice (e.g., antacids, such as aluminum hydroxide, or products that inhibit the secretion of hydrochloric acid, such as H2-histamine receptor antagonists and proton pump inhibitors), impair the absorption of the drug Itraconazole. It is recommended to use these medicinal agents with caution in combination with itraconazole:
– Itraconazole is recommended to be taken together with acidic beverages (such as non-diet Coke) when using medicinal agents that reduce the acidity of gastric juice together.
– It is recommended to take medicines that neutralize hydrochloric acid (such as aluminum hydroxide) at least 1 hour before or 2 hours after taking Itraconazole.
When co-administering medications, it is recommended that the antifungal activity of itraconazole be monitored and the dose of the drug be increased as needed.
The co-administration of itraconazole with strong inducers of CYP3A4 isoenzyme may decrease the bioavailability of itraconazole and hydroxyitraconazole to the extent that the effectiveness of the medicine will be reduced. Examples include the following drugs:
– Antibacterials: isoniazid, rifabutin, rifampicin.
– Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
– Antiviral drugs: efavirenz, nevirapine.
Hence, the use of strong inducers of CYP3A4 isoenzyme in combination with itraconazole is not recommended. It is recommended to avoid taking these medicinal agents for 2 weeks before starting to take itraconazole and during treatment with the drug, except in cases when the expected benefits exceed the potential risk associated with a decrease in the effectiveness of itraconazole. It is recommended to monitor the antifungal activity of itraconazole during concomitant use of the medicinal product, and to increase the dose of the drug if necessary.
Drugs which may cause increase in plasma concentration of itraconazole
The simultaneous use of itraconazole and strong CYP3A4 isoenzyme inhibitors may lead to increased bioavailability of itraconazole. Examples of strong inhibitors of CYP3A4 isoenzyme:
– Antibacterial drugs: ciprofloxacin, clarithromycin, erythromycin.
– Antiviral drugs: darunavir, ritonavir-enhanced, fosamprenavir, ritonavir-enhanced, indinavir, ritonavir and telaprevir.
These medications are recommended with caution when used with itraconazole. It is recommended to monitor closely the condition of patients taking itraconazole together with strong CYP3A4 isoenzyme inhibitors, for timely detection of symptoms and signs of enhancement or prolongation of pharmacological effects of itraconazole, if necessary, itraconazole dose reduction is possible. If possible, it is recommended to monitor the plasma concentration of itraconazole.
Drugs the plasma concentrations of which may increase when combined with itraconazole
Itraconazole and its main metabolite hydroxyitraconazole may interfere with the metabolism of drugs metabolized by CYP3A4 isoenzyme and inhibit the transportation of drugs by P-glycoprotein. This may lead to increased plasma concentrations of these drugs and/or their active metabolites when co-administered with itraconazole. The increase of plasma concentration, in turn, can cause intensification or prolongation of both therapeutic and undesirable effects of these drugs, which can result in potentially life-threatening conditions. Thus, increased concentrations of some drugs (terfenadine, astemizole, bepridil, misolastin, cisapride, dofetilide, quinidine, pimozide, sertindol, levometadone) may lead to increased QT interval and ventricular tachyarrhythmias, including cases of ventricular pirouette tachycardia, which are considered potentially life-threatening conditions. After discontinuation of treatment, plasma concentrations of itraconazole decrease to near indeterminate levels within 7 to 14 days, depending on the drug dose and duration of treatment. In patients with cirrhosis or those who concomitantly take CYP3A4 enzyme inhibitors the decrease in drug concentration may be even slower. This is especially important during the initiation of therapy with the use of drugs, metabolism of which is affected by itraconazole.
The concomitant medications fall into the following categories:
– “Contraindicated”: Under no circumstances should this medication be used in combination with itraconazole and for 2 weeks after stopping itraconazole.
“Not recommended”: It is recommended to avoid the use of this medicine during treatment and for 2 weeks after discontinuation of itraconazole, unless the expected benefits exceed the potential risks associated with the current therapy. If it is impossible to avoid using this combination of medicinal agents, it is recommended to monitor the patient’s condition for timely detection of symptoms and signs of intensification or prolongation of drug effects or development of side effects; if necessary, the treatment may be interrupted or the dose of medicinal agents may be reduced. If possible, it is recommended that plasma concentrations of the drugs be monitored.
– Use with caution: Close monitoring should be done when using the drug together with itraconazole. When concomitant use of the medicinal products it is recommended to monitor the patient’s condition for timely detection of symptoms and signs of intensification or prolongation of drug effects or development of side effects; if necessary, treatment may be interrupted or the dose of the medicinal products may be reduced. If possible, it is recommended to monitor the plasma concentration of the drugs.
The following are examples of medications that can increase plasma concentrations with itraconazole. The drugs are divided into classes, and recommendations are also given for combined use with itraconazole:
Drug class | Contraindicated | Not recommended | Use with caution | ||
Alpha-adrenoblockers | Tamsulosin | ||||
Narcotic analgesics | Levacetylmethadol (levomethadil), methadone | Fentanyl | Alfentanil, buprenorphine for intravenous and sublingual administration, oxycodone, sufentanil | ||
Antiarrhythmic agents | Disopyramide, dofetilide, dronedarone, quinidine | ||||
Antibacterials | Telithromycin in patients with severe renal or hepatic impairment | Telithromycin in patients with severe renal or hepatic impairment | Rifabutina | Telithromycin | |
Anticoagulants and antiaggregants | Ticagrelor | Apixaban, rivaroxaban | Coumarins, cilostazol, dabigatran | ||
Anticonvulsants | /td> | Carbamazepinea | |||
Antidiabetic drugs | |||||
Anthelminthic and antiprotozoal agents < | Halofantrine | Praziquantel | |||
Antihistamines /td> | Astemizole, misolastin, terfenadine | Bilastin, ebastine | |||
Migraine medications | Etrone alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methyl ergometrine (methyl ergonovine), eletriptan | ||||
Antitumor drugs | Irinotecan | Axitinib, dafrafenib, dasatinib, ibrutinib, nilotinib sunitinib, trabectedin < | Bortezomib, buzulfan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, periwinkle alkaloids /td> | ||
Neuroleptics, anxiolytics, and hypnotics | Lurazidone, oral midazolam, pimozide, sertindol, triazolam | Alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, intravenous midazolam, perosapine, quetiapine, ramelteon, risperidone | |||
Antiviral drugs | Maraviroc, indinavirb, ritonavirb, saquinavir | ||||
Beta-adrenal blockers < | Nadolol | ||||
Slow calcium channel blockers “slow” calcium channels | Bepridil, felodipine, lercanidipine, nisoldipine | ||||
Other drugs acting on the cardiovascular system | Ivabradine, ranolazine | Aliskiren, sildenafil in the treatment of pulmonary hypertension | Bosentan, riociguat | ||
Diuretics | Eplerenone | ||||
Drugs affecting the gastrointestinal tract | Cisapride, domperidone | Aprepitant | |||
Immunosuppressants | Everolimus | Budesonide, cyclasonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus, temsirolimus | |||
Drugs that regulate lipid metabolism |
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Drugs used to treat respiratory diseases | Salmeterol | ||||
Reboxetine | |||||
Drugs used in urology | Fesoterodine in patients with moderate to severe renal or hepatic function impairment, solifenacin in patients with severe renal function impairment and moderate to severe hepatic function impairment | Darifenacin, vardenafil | Phesoterodine, imidafenacin, oxybutynin, sildenafil in the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine | ||
Others | Colchicine in patients with impaired liver or kidney function | Colchicine, conivaptan, tolvaptan | Alitretinoin (oral dosage forms), cinacalcet, mosavaptan. |
a See also “Drugs that may decrease plasma concentrations of itraconazole”.
b See also “Drugs that may increase the plasma concentration of itraconazole”.
Drugs whose plasma concentrations may be decreased by itraconazole
The concomitant use of itraconazole with the nonsteroidal anti-inflammatory drug meloxicam may decrease the plasma concentration of meloxicam. It is recommended with caution to prescribe meloxicam concomitantly with itraconazole, as well as to monitor closely the clinical condition of the patient and the occurrence of side effects. The dose of meloxicam should be adjusted if necessary.
Children
Drug interactions have only been studied in adults.
Special Instructions
In a study of itraconazole in intravenous dosage form, a transient asymptomatic decrease in left ventricular ejection fraction was observed, which normalized before the next infusion of the drug. The clinical significance of these findings for oral dosage forms is unknown.
Itraconazole has a negative inotropic effect. There have been reported cases of chronic heart failure associated with taking itraconazole. At a daily dose of 400 mg of itraconazole, a more frequent occurrence of heart failure was observed; no such pattern was found at lower daily doses. The risk of chronic heart failure is presumably proportional to the daily dose. The drug should not be used in patients with chronic heart failure or with the presence of this symptom complex in the anamnesis, except in cases when the possible benefit significantly exceeds the potential risk. In individual assessment of the benefit-risk ratio such factors as severity of indications, dosage regimen and individual risk factors of heart failure (coronary heart disease, valve lesions, obstructive pulmonary disease, renal failure and other diseases accompanied by edema) should be taken into account. Such patients should be informed about signs and symptoms of chronic heart failure and follow their appearance during the treatment. If such signs appear, the drug should be discontinued.
Life-threatening cardiac arrhythmias and/or sudden death have been reported in patients with concomitant use of methadone.
Medication interactions: simultaneous use of some medicinal products with itraconazole can lead to changes in the effectiveness of itraconazole and/or concomitant drugs, occurrence of life-threatening adverse reactions and/or sudden death. Drugs that should not be taken concomitantly with itraconazole, not recommended for concomitant use and/or recommended for concomitant use with itraconazole with caution are listed in section “Interaction with other medicinal products”.
Cross hypersensitivity: there are limited data on the presence of cross-sensitivity between itraconazole and other antifungal agents with azole structure (from the group of azoles). In the presence of hypersensitivity to other azoles, itraconazole should be used with caution.
Interchangeability: interchangeable use of itraconazole in the form of capsules and in the form of oral solution is not recommended, due to the fact that exposure to itraconazole is higher when used in the form of oral solution than in the form of capsules, even when the same doses of itraconazole are taken.
Decreased gastric acidity: absorption of itraconazole from capsules is impaired when gastric acidity is decreased. In patients with decreased gastric acidity due to a disease (e.g., in patients with achlorhydria) or due to taking medications (e.g., drugs that inhibit gastric secretion), itraconazole is recommended to take it simultaneously with acidic beverages (such as non-dietic cola). The antifungal activity of the drug should be monitored and the dose of itraconazole should be increased if necessary.
Impact on liver function: In very rare cases severe toxic liver damage developed during the use of the drug, including several cases of acute hepatic failure with fatal outcome. In most cases this occurred in patients who already had liver disease, in patients with other severe diseases to whom the drug was prescribed for the treatment of systemic diseases, as well as in patients who received other drugs with hepatotoxic effects. However, some patients had no comorbidities or obvious risk factors for liver damage. Several such cases occurred in the first month of therapy, and some in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy. In case of symptoms suggestive of hepatitis occurrence, namely: anorexia, nausea, vomiting, weakness, abdominal pain and darkened urine, it is necessary to stop treatment immediately and conduct liver function tests. Patients with increased “liver” enzymes activity or active liver disease, or in patients with past toxic liver injury caused by taking other drugs should not be treated with itraconazole, except in cases when the expected benefits justify the risk of liver damage. In such cases, it is necessary to monitor the activity of “liver” enzymes during treatment. Itraconazole is mainly metabolized in the liver. As the total half-life of itraconazole in patients with liver dysfunction is slightly prolonged, itraconazole plasma concentrations should be controlled and the dose of the medicine adjusted, if necessary.
With impaired renal function: the data on the use of the drug in patients with renal impairment are limited, and in some patients with renal impairment the exposure to itraconazole may be reduced. Therefore, the drug should be administered with caution in such patients. It is recommended to monitor the concentrations of itraconazole in plasma and adjust the dose of the drug, if necessary.
Patients with immunodeficiency: bioavailability of itraconazole in per oral administration may be reduced in some patients with impaired immunity, such as patients with neutropenia, patients with AIDS or patients who underwent surgery for organ transplantation.
Patients with systemic fungal infections that are life-threatening: Due to the pharmacokinetic characteristics of itraconazole, its use is not recommended for initiating treatment of systemic mycoses that are life-threatening in patients.
AIDS patients: The treating physician should evaluate the need for maintenance therapy in AIDS patients previously treated for systemic fungal infections such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and nonmeningeal) who are at risk for relapse.
Pediatric use: Because there is insufficient clinical data on the use of itraconazole in children, it is recommended that the drug be administered to children only if the possible benefit of treatment outweighs the potential risk.
Women of childbearing age who are taking itraconazole should use adequate contraception for the duration of treatment until their first menstrual period after treatment ends.
The treatment should be stopped if peripheral neuropathy occurs, which may be associated with the use of Itraconazole.
In systemic candidiasis suspected to be caused by fluconazole-resistant strains of Candida, sensitivity to itraconazole cannot be assumed, therefore, it is recommended to check sensitivity before starting itraconazole therapy.
Hearing loss: Temporary or permanent hearing loss has been reported in patients taking itraconazole. In some cases, hearing loss occurred while concomitant use with quinidine (see sections “Contraindications” and “Interaction with other medicinal products”). Hearing usually returns after therapy with Itraconazole, but some patients have irreversible hearing loss.
Confertility: animal studies have shown no reproductive toxicity in itraconazole.
Mucoviscidosis (cystic fibrosis): In patients with cystic fibrosis (cystic fibrosis) a variability in plasma concentration of itraconazole was observed when using itraconazole in the form of oral solution at a dose of 2.5 mg/kg 2 times daily. As a consequence, the therapeutic equilibrium plasma concentration of itraconazole may not be reached. Equilibrium concentrations of >250 ng/ml were achieved in approximately 50% of patients over the age of 16 years and were not achieved in any patient younger than 16 years. If there is no response to therapy with Itraconazole, consideration should be given to switching to an alternative therapy.
Influence on ability to drive vehicles, mechanisms
There have been no studies on the effect of itraconazole on the ability to drive vehicles and operate machinery. It is necessary to take into account the possibility of adverse reactions, such as dizziness, visual impairment and hearing loss (see “Adverse effects”). If the adverse events described above occur, you should refrain from performing the indicated activities.
Synopsis
Solid gelatin capsules № 0 opaque pink with a blue cap. The content of the capsules – spherical microgranules (pellets) from white to cream color.
Contraindications
- Hypersensitivity to itraconazole or excipients. Interaction with other medicinal products), such as:
– levacetylmethadol, methadone;
– disopyramide, dofetilide, dronedarone, quinidine;
– telithromycin in patients with severe renal or hepatic impairment;
– ticagrelor;
– halofantrine;
– astemizole, misolastin, terfenadine;
– ergot alkaloids: dihydroergotamine, ergometrine (ergonovine), ergotamine, methyl ergometrine (methyl ergonovine), eletriptan;
– irinotecan;
– lurazidone, oral midazolam, pimozide, sertindol, triazolam;
-bepridil, felodipine, lercanidipine, nisoldipine;
– ivabradine, ranolazine;
– eplerenone;
– cisapride, domperidone;
p> – lovastatin, simvastatin, atorvastatin;
Fesoterodine in patients with moderate to severe renal or hepatic impairment, solifenacin in patients with severe renal impairment and moderate to severe hepatic impairment;
– Colchicine in patients with impaired hepatic or renal function.
- Cronic heart failure current or history (except for therapy of life-threatening or other dangerous infections see “Special Indications”).
- Fructose intolerance, sucrose/isomaltase deficiency, glucose-galactose malabsorption.
- Children under 3 years of age.
- Pregnancy and breastfeeding.
With caution
In cirrhosis; severe hepatic and renal dysfunction; hypersensitivity to azoles; in elderly patients; in children.
Side effects
According to the World Health Organization (WHO), adverse effects are classified according to their frequency of occurrence as follows: Very common (≥1/10), common (>1/100 and <1/10), infrequent (>1/1000 and <1/100), rare (>1/10000 and <1/1000) and very rare (<1/10000), including isolated cases; frequency unknown – cannot be calculated from available data.
Data from clinical trials
107 open-label and double-blind clinical trials involving 8,499 patients where all patients took itraconazole at least once were evaluated for treatment safety.
Infectious and parasitic diseases:
Infrequent: rhinitis, sinusitis, upper respiratory tract infections.
Disorders of the hematopoietic and lymphatic systems:
Rarely: leukopenia;
Frequently unknown: neutropenia.
Immune system disorders:
Infrequent: hypersensitivity.
Nervous system disorders:
Often: headache;
Rarely: hypoesthesia, paresthesia.
Hearing organ and labyrinth disorders:
Rarely: tinnitus.
Gastrointestinal disorders:
Often: abdominal pain, nausea;
Infrequently: dyspepsia, constipation, flatulence, diarrhea, vomiting;
Rarely: dysgeusia.
Liver and biliary tract disorders:
Infrequent: hyperbilirubinemia, liver dysfunction.
Skin and subcutaneous fatty tissue disorders:
Infrequent: rash, itching, urticaria.
Renal and urinary tract disorders:
Rare: pollakiuria.
Reproductive system and mammary gland disorders:
Infrequently: menstrual disorders;
Rarely: erectile dysfunction.
General complications and reactions at the injection site:
Rarely: edema syndrome.
Below is a list of adverse reactions associated with the administration of itraconazole in the form of oral solution and/or solution for intravenous injection (excluding adverse reactions classified as “inflammation at the injection site”, because these adverse reactions are specific to the dosage form “solution for intravenous injection”).
Disorders of the hematopoietic and lymphatic systems:
Granulocytopenia, thrombocytopenia.
Disorders of the immune system:
Anaphylactoid reactions.
Metabolic disorders:
Hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia.
Mental disorders:
Confusion.
Nervous system disorders:
Peripheral neuropathy, dizziness, somnolence.
Cardiovascular system disorders:
Heart failure, left ventricular insufficiency, tachycardia, arterial hypertension, arterial hypotension.
Respiratory system, thoracic and mediastinal organs:
Lung edema, dysphonia, cough.
Gastrointestinal tract disorders:
Gastrointestinal disorders.
Disorders of liver and biliary tract:
Hepatitis, jaundice, liver function disorders.
Disorders of skin and subcutaneous tissue:
Erythematous rash, hyperhidrosis.
Musculoskeletal and connective tissue disorders:
Myalgia, arthralgia.
Renal and urinary tract disorders:
Renal dysfunction, urinary incontinence.
General disorders and disorders at the site of administration:
Generalized edema, facial edema, chest pain, hyperthermia, pain, fatigue, chills.
Effect on the results of laboratory parameters and instrumental studies:
Increased alanine aminotransferase activity, increased aspartate aminotransferase activity, increased alkaline phosphatase activity in plasma, increased lactate dehydrogenase activity in plasma, increased blood urea concentration, increased gamma-glutamyltransferase activity, increased liver enzymes activity, deviation from normal urinalysis.
Children
The safety of itraconazole was evaluated in 14 clinical trials (4 double-blind, placebo-controlled studies, 9 open-label studies, and 1 with an open phase followed by double-blind studies) involving 165 children aged 1 to 17 years. The studies noted that the most common adverse reactions were: headache, vomiting, abdominal pain, diarrhea, impaired liver function, nausea, and urticaria. The nature of adverse reactions encountered in children is similar to that observed in adult patients; however, the frequency of adverse reactions in children is higher.
Adverse effects reported in the post-registration period (data obtained from spontaneous reports)
The reported frequency of adverse reactions is based on clinical experience with itraconazole in capsule form after registration.
Immune system disorders:
Very rare: serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.
Metabolic disorders:
Very rare: hypertriglyceridemia.
Nervous system disorders:
Very rare: tremor.
Visually impaired:
Very rare: blurred vision, diplopia.
Hearing and labyrinth disorders:
Very rare: persistent or temporary hearing loss.
Cardiovascular system disorders:
Very rare: chronic heart failure.
Respiratory system:
Often: shortness of breath.
Gastrointestinal tract:
Very rare: pancreatitis.
Hepatobiliary system:
Very rare: severe toxic liver damage (including several cases of acute liver failure with fatal outcome).
Skin and subcutaneous fatty tissue:
Very rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.
Effect on the results of laboratory parameters and instrumental studies:
Very rare: increased blood creatine phosphokinase activity.
Overdose
The symptoms observed in itraconazole overdose were comparable to the dose-dependent adverse reactions observed with normal doses of the drug.
Treatment
There is no specific antidote. In case of overdose, supportive therapy should be carried out, gastric lavage with sodium bicarbonate solution, give activated charcoal. Itraconazole is not eliminated from the body by hemodialysis.
Pregnancy use
Pregnancy
Itraconazole should not be used in pregnancy, except in life-threatening cases and if the expected positive effect on the mother exceeds the possible harm to the fetus.
In preclinical studies, itraconazole has been shown to have reproductive toxicity. There is insufficient data on the use of itraconazole during pregnancy. Cases of congenital abnormalities were noted during the clinical use of the drug after registration. Such cases included abnormalities of the visual, skeletal, genitourinary, and cardiovascular systems, as well as chromosomal abnormalities and multiple malformations. However, whether the use of itraconazole causes these disorders has not been reliably established.
Epidemiologic data regarding exposure to itraconazole in the first trimester of pregnancy, primarily in patients receiving short-term therapy for vulvovaginal candidiasis, did not show an increased risk of congenital abnormalities compared to a control group not exposed to any of the known teratogenic factors.
Women of childbearing age taking itraconazole should use highly effective contraception for the duration of treatment until their first menstrual period after completion of treatment.
Breast-feeding period
Very little itraconazole is excreted with the breast milk. When prescribing itraconazole to women who breastfeed, it is necessary to weigh the expected balance of benefits and risks. In case of doubts, the woman should stop breastfeeding.
Similarities
Irunin, Rumicose, Itrazol, Orungamin, Itraconazole
Weight | 0.018 kg |
---|---|
Shelf life | 3 years. Do not use after the expiration date stated on the package. |
Conditions of storage | In a dry, light-protected place at a temperature not exceeding 25 °C. Store out of the reach of children. |
Manufacturer | Biocom AO, Russia |
Medication form | capsules |
Brand | Biocom AO |
Other forms…
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