Canditral^® (Capsules) Instructions for Use

Marketing Authorization Holder

Glenmark Pharmaceuticals, Ltd. (India)

Contact Information

GLENMARK IMPEX LLC (Russia)

ATC Code

J02AC02 (Itraconazole)

Active Substance

Itraconazole (Rec.INN registered by WHO)

Dosage Form

Canditral®

Capsules 100 mg: 4, 6, 7, or 14 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, with a red body and a white cap, with the inscription “Canditral” on the body and the company logo on the cap; capsule contents – shiny pellets from white to white, odorless.

* 1 caps. contains itraconazole pellets – 498.65 mg.

Excipients: hypromellose (hydroxypropyl methylcellulose), methyl methacrylate, dimethylaminoethyl methacrylate and butyl methacrylate copolymer (eudragit E-100), sucrose, macrogol 20000 (polyethylene glycol 20000).

Composition of the capsule cap gelatin, purified water, methylparahydroxybenzoate (methylparaben), propylparahydroxybenzoate (propylparaben), sodium lauryl sulfate, dye titanium dioxide, dye iron oxide black (for applying the company logo “G”).
Composition of the capsule body gelatin, purified water, methylparahydroxybenzoate (methylparaben), propylparahydroxybenzoate (propylparaben), sodium lauryl sulfate, dye ponceau 4R, dye azorubine (carmoisine), titanium dioxide (for the inscription “canditral”).

4 pcs. – blister packs (1) – sealed bags made of aluminum laminate (1) – cardboard packs.
6 pcs. – blister packs (1) – sealed bags made of aluminum laminate (1) – cardboard packs.
7 pcs. – blister packs (1) – sealed bags made of aluminum laminate (1) – cardboard packs.
7 pcs. – blister packs (1) – sealed bags made of aluminum laminate (2) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

Itraconazole is a synthetic broad-spectrum antifungal agent, a triazole derivative.

The mechanism of action of itraconazole is the inhibition of the biosynthesis of ergosterol, the main component of the fungal cell membrane, which is involved in maintaining the structural integrity of the membrane.

Violation of ergosterol synthesis leads to a change in membrane permeability and cell lysis, which determines the 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 Candida albicans, Candida tropicalis, Candida parapsilosis, Candida krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including Histoplasma 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 suppressed by itraconazole are Zygomycetes (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.

The described mechanisms of resistance development include hyperexpression of the ERG11 gene, which encodes the enzyme 14α-demethylase, which is the main target of azole action, and point mutations in ERG11, leading to a decrease in enzyme binding to azoles and/or activation of transport systems, which leads to increased excretion of azoles.

Cross-resistance of Candida spp. to drugs of the azole group has been observed, although resistance to one drug of this group does not necessarily mean resistance to other drugs of the azole group.

Strains of Aspergillus fumigatus resistant to itraconazole have been reported.

Pharmacokinetics

Due to nonlinear pharmacokinetics, Itraconazole accumulates in blood plasma with repeated administration.

The C_ss of itraconazole is generally reached within approximately 15 days, with the C_max and AUC values of itraconazole with repeated administration being 4-7 times higher than with a single dose.

The maximum equilibrium concentration of itraconazole in plasma (C_ss,max) is about 2 μg/ml when 200 mg of itraconazole is administered once/day.

The final T_1/2 is usually 16-28 hours with a single dose and 34-42 hours with repeated doses.

The concentration of itraconazole in blood plasma decreases to almost undetectable levels within 7-14 days after the end of therapy, depending on the prescribed dose and duration of treatment.

The clearance of itraconazole decreases at higher doses due to saturation of its metabolic pathways in the liver.

Absorption

Itraconazole is rapidly absorbed after oral administration.

C_max of unchanged itraconazole in plasma is reached within 2-5 hours after oral administration.

The absolute bioavailability of itraconazole after oral administration is about 55%.

With oral use, the maximum bioavailability of itraconazole is noted when taking capsules immediately after a meal.

The absorption of itraconazole in capsules is reduced in patients with reduced gastric acidity, for example, while taking drugs that suppress the secretion of hydrochloric acid in the stomach (such as H₂-histamine receptor antagonists, proton pump inhibitors), or in patients with achlorhydria due to various diseases.

The absorption of itraconazole on an empty stomach in such patients increases when taking itraconazole capsules simultaneously with acidic drinks (such as non-diet cola).

When taking itraconazole capsules at a dose of 200 mg once on an empty stomach with non-diet cola after preliminary administration of the H₂-histamine receptor antagonist ranitidine, the absorption of itraconazole was comparable to the absorption of itraconazole capsules when taking only this drug.

Distribution

Itraconazole is 99.8% bound to plasma proteins, mainly albumin (hydroxyitraconazole is 99.6% bound to albumin).

An affinity for lipids has also been noted.

Only 0.2% of itraconazole remains unbound in plasma.

The apparent V_d is >700 L, which indicates its significant distribution in tissues.

Concentrations in the lungs, kidneys, bones, stomach, spleen and muscles are 2-3 times higher than the corresponding plasma concentrations, while the concentration of the drug in tissues containing keratin, especially in the skin, is approximately 4 times higher than the concentration in plasma.

The concentration in the cerebrospinal fluid is significantly lower than in blood plasma, nevertheless, the effectiveness of itraconazole against pathogens present in the 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 many metabolites.

The main metabolite is hydroxyitraconazole, which in vitro has antifungal activity comparable to itraconazole.

Plasma concentrations of hydroxyitraconazole are approximately 2 times higher than the concentration of itraconazole.

Excretion

Based on the results of a study of the pharmacokinetics of ¹⁴C-labeled drug after oral administration, the excretion of unchanged itraconazole in feces ranges from 3% to 18% of the dose taken.

Since the redistribution of itraconazole from tissues containing keratin is insignificant, the excretion of itraconazole from these tissues is associated with epidermal regeneration.

Unlike blood plasma, the concentration of itraconazole in the skin persists for 2 to 4 weeks after stopping 4-week treatment, and the concentration in nail keratin, where Itraconazole can be detected as early as 1 week after starting treatment, persists for at least 6 months after the end of a 3-month course of treatment.

Pharmacokinetics in special patient groups

Impaired liver function. Itraconazole is predominantly metabolized in the liver.

During a pharmacokinetic study, the pharmacokinetic parameters of patients with liver cirrhosis and healthy volunteers were compared.

In patients with liver cirrhosis after a single dose of 100 mg of itraconazole, the mean C_max of itraconazole in plasma was significantly lower (by 47%) than in healthy patients.

The mean T_1/2 after a single dose was increased in patients with liver cirrhosis and in this study was 37±17 hours compared to 16±5 hours for healthy volunteers.

The mean exposure of itraconazole (AUC) was similar in patients with liver cirrhosis and in healthy volunteers.

There are no data on the long-term use of itraconazole in patients with liver cirrhosis (see sections “Dosage Regimen” and “Special Instructions”).

Impaired renal function. Data on the oral use of itraconazole for the treatment of patients with impaired renal function are limited.

In patients with uremia, whose mean CC was 13 ml/min × 1.73 m², the systemic exposure of itraconazole (AUC) was somewhat lower compared to the main population.

No significant effect of hemodialysis or long-term peritoneal dialysis performed on an outpatient basis on the pharmacokinetic parameters of itraconazole (T_max, C_max and AUC_0-8h) was identified.

After a single IV administration of the drug, the final T_1/2 of itraconazole in patients with mild (defined in the study as CC 50-79 ml/min), moderate (CC 20-49 ml/min) or severe renal impairment (CC < 20 ml/min) was similar to that in healthy people (range of mean values 42-49 hours compared to 48 hours in patients with renal impairment and healthy volunteers, respectively).

The total exposure of itraconazole, based on the AUC assessment, was reduced in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, compared with patients with normal renal function.

Data on the long-term use of itraconazole by patients with impaired renal function are not available.

Dialysis does not affect the T_1/2 or clearance of itraconazole or hydroxyitraconazole.

Children. Data on the pharmacokinetics of itraconazole in pediatric patients are limited.

Indications

Lesions of the skin and mucous membranes

• Vulvovaginal candidiasis;
• Pityriasis versicolor;
• Dermatomycoses;
• Candidiasis of the oral mucosa;
• 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 CNS cryptococcosis, Canditral^® should be prescribed only in cases where first-line drugs are not applicable in this case or are ineffective);
• Histoplasmosis;
• Blastomycosis;
• Sporotrichosis;
• Paracoccidioidomycosis;
• Other rare systemic or tropical mycoses.

ICD codes

Dosage Regimen

For optimal absorption of the drug, Canditral^® should be taken immediately after a meal. Capsules should be swallowed whole.

Onychomycosis caused by dermatophytes and/or yeasts, mold fungi

The elimination of itraconazole from the skin and nail tissue is slower than from plasma. Thus, the optimal clinical and mycological effect is 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

* The duration of treatment may be adjusted depending on the treatment efficacy.

Special patient groups

Data on the use of Canditral^®, capsules, for the treatment of children are limited. The use of the drug for the treatment of children is not recommended, except in cases where the expected benefit of treatment outweighs the potential risk.

Data on the use of Canditral^®, capsules, for the treatment of elderly patients are limited. It is recommended to use the drug for the treatment of patients in this category only if the expected benefit of treatment exceeds the potential risk. When choosing the dose of the drug for the treatment of elderly patients, it is recommended to take into account the reduced function of the liver, kidneys, and heart, which are more common in old age, as well as the presence of concomitant diseases or the use of other medications.

Data on the use of itraconazole in capsule form in patients with impaired liver function are limited. The drug should be prescribed with caution to this category of patients.

Data on the use of itraconazole in capsule form in patients with impaired renal function are limited. In some patients with renal failure, the exposure to itraconazole may be reduced. The drug should be prescribed with caution to this category of patients; in some cases, an adjustment of the drug dose may be required.

Adverse Reactions

Adverse reactions of the drug are classified by system organ class according to the frequency of occurrence as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated cases; frequency unknown (cannot be estimated from the available data).

Data obtained from clinical trials

The safety of itraconazole in capsule form was studied in 107 open and double-blind clinical trials involving 8499 patients. All 8499 patients took Itraconazole in capsule form at least once, after which the safety of treatment was assessed.

Infections and infestations uncommon – rhinitis, sinusitis, upper respiratory tract infections.

Blood and lymphatic system disorders rare – leukopenia; frequency unknown – neutropenia.

Immune system disorders uncommon – hypersensitivity.

Nervous system disorders common – headache; rare – hypoesthesia, paresthesia.

Ear and labyrinth disorders rare – tinnitus.

Gastrointestinal disorders common – abdominal pain, nausea; uncommon – dyspepsia, constipation, flatulence, diarrhea, vomiting; rare – dysgeusia.

Hepatobiliary disorders uncommon – hyperbilirubinemia, impaired liver function.

Skin and subcutaneous tissue disorders uncommon – rash, pruritus, urticaria.

Renal and urinary disorders rare – pollakiuria.

Reproductive system and breast disorders uncommon – menstrual cycle disorder; rare – erectile dysfunction.

General disorders and administration site conditions rare – edema syndrome.

The following is a list of adverse reactions associated with the intake of itraconazole, which were registered in clinical trials of itraconazole in oral solution and/or intravenous solution form (with the exception of adverse reactions related to the category of “inflammation at the injection site”, since these adverse reactions are specific to the intravenous solution dosage form).

Blood and lymphatic system disorders granulocytopenia, thrombocytopenia.

Immune system disorders anaphylactoid reactions.

Metabolism and nutrition disorders hyperglycemia, hyperkalemia, hypokalemia, hypomagnesemia.

Psychiatric disorders confusion.

Nervous system disorders peripheral neuropathy, dizziness, somnolence.

Cardiac disorders heart failure, left ventricular failure, tachycardia, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders pulmonary edema, dysphonia, cough.

Gastrointestinal disorders gastrointestinal disorders.

Hepatobiliary disorders hepatitis, jaundice, impaired liver function.

Skin and subcutaneous tissue disorders erythematous rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders myalgia, arthralgia.

Renal and urinary disorders renal function failure, urinary incontinence.

General disorders and administration site conditions generalized edema, facial edema, chest pain, hyperthermia, pain, fatigue, chills.

Investigations increased ALT activity, increased AST activity, increased plasma alkaline phosphatase activity, increased plasma LDH activity, increased blood urea concentration, increased GGT activity, increased hepatic enzyme activity, abnormal urinalysis parameters.

Children

The safety of itraconazole in capsule form was evaluated in 14 clinical trials (4 double-blind, placebo-controlled trials, 9 open trials, and 1 trial with an open phase followed by a double-blind phase) involving 165 children aged 1 to 17 years. During the trials, it was noted that the most frequently occurring adverse reactions were: headache, vomiting, abdominal pain, diarrhea, impaired liver function, nausea, urticaria. The nature of adverse reactions occurring in children is similar to that observed in adult patients; however, the frequency of adverse reactions in children is higher.

Adverse reactions reported during the post-marketing period (data obtained from spontaneous reports)

The presented frequency of adverse reactions is based on the clinical experience of itraconazole use after registration.

Immune system disorders very rare – serum sickness, angioedema, anaphylactic, anaphylactoid and allergic reactions.

Metabolism and nutrition disorders very rare – hypertriglyceridemia.

Nervous system disorders very rare – tremor.

Eye disorders very rare – blurred vision, diplopia.

Ear and labyrinth disorders very rare – persistent or temporary hearing loss.

Cardiac disorders very rare – chronic heart failure.

Respiratory, thoracic and mediastinal disorders common – dyspnea.

Gastrointestinal disorders very rare – pancreatitis.

Hepatobiliary disorders very rare – severe toxic liver damage (including several cases of acute liver failure with fatal outcome).

Skin and subcutaneous tissue disorders very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity.

Investigations very rare – increased blood CPK activity.

Contraindications

• Hypersensitivity to itraconazole or excipients;
• Concomitant use of drugs that are substrates of the CYP3A4 isoenzyme (see section “Drug Interactions”), such as:
  • Levacetylmethadol, methadone;
  • Disopyramide, dofetilide, dronedarone, quinidine;
  • Telithromycin in patients with severe renal or hepatic impairment;
  • Ticagrelor;
  • Halofantrine;
  • Astemizole, mizolastine, terfenadine;
  • Ergot alkaloids: dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), eletriptan;
  • Irinotecan;
  • Lurasidone, orally administered midazolam, pimozide, sertindole, triazolam;
  • Bepridil, felodipine, lercanidipine, nisoldipine;
  • Ivabradine, ranolazine;
  • Eplerenone;
  • Cisapride, domperidone;
  • Lovastatin, simvastatin, atorvastatin;
  • Fesoterodine in patients with moderate or severe renal or hepatic impairment, solifenacin in patients with severe renal impairment and moderate or severe hepatic impairment;
  • Colchicine in patients with impaired liver or kidney function.
• Current or history of chronic heart failure (except for the therapy of life-threatening or other dangerous infections (see section “Special Precautions”);
• Fructose intolerance, sucrase/isomaltase deficiency, glucose-galactose malabsorption;
• Children under 3 years of age;
• Pregnancy;
• Breastfeeding period.

With caution in liver cirrhosis; severe impairment of liver and kidney function; hypersensitivity to other azoles; in elderly patients; in children (see also section “Special Precautions”).

Use in Pregnancy and Lactation

Pregnancy

Itraconazole should not be used during pregnancy, except in life-threatening situations and if the expected positive effect for the mother outweighs the possible harm to the fetus.

Preclinical studies have shown that Itraconazole crosses the placental barrier in rats.

Data on the use of itraconazole in capsule form during pregnancy are insufficient.

During the post-marketing clinical use of the drug, cases of congenital anomalies have been reported. Such cases included developmental disorders of the visual, skeletal, genitourinary and cardiovascular systems, as well as chromosomal abnormalities and multiple malformations. However, whether the use of itraconazole in capsule form is the cause of these disorders has not been reliably established. Epidemiological data regarding exposure to itraconazole in capsule form in the first trimester of pregnancy, mainly in patients receiving short-term therapy for vulvovaginal candidiasis, did not reveal an increased risk of congenital anomalies compared to the control group not exposed to any known teratogenic factors.

Women of childbearing potential taking Itraconazole in capsule form must use adequate methods of contraception throughout the course of treatment until the first menstruation after its completion.

Breastfeeding

Since Itraconazole can pass into breast milk, if it is necessary to use the drug during lactation, women using Itraconazole in capsule form should stop breastfeeding.

Use in Hepatic Impairment

The drug should be prescribed with caution in liver cirrhosis, severe impairment of liver function.

Use in Renal Impairment

The drug should be prescribed with caution in severe impairment of renal function.

Pediatric Use

The use of the drug is contraindicated in children under 3 years of age.

Since clinical data on the use of Canditral^® in children are insufficient, it is recommended to prescribe the drug to children only if the possible benefit of treatment outweighs the potential risk.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Itraconazole has a negative inotropic effect. Cases of chronic heart failure associated with the use of Canditral^® have been reported. When using itraconazole at a daily dose of 400 mg, a more frequent occurrence of heart failure was observed; with lower daily doses, such a pattern was not identified. The risk of congestive heart failure is presumably proportional to the daily dose. Canditral^® should not be taken by patients with chronic heart failure (including history), except in cases where the possible benefit significantly outweighs the potential risk. When individually assessing the benefit-risk ratio, factors such as the severity of the indication, the dosing regimen and individual risk factors for heart failure (coronary artery disease, valvular disease, obstructive pulmonary diseases, renal failure and other diseases accompanied by edema) should be taken into account. Such patients should be informed about the signs and symptoms of chronic heart failure and monitored for their appearance during the course of treatment. If such signs appear, the use of Canditral^® should be discontinued.

Life-threatening cardiac arrhythmias and/or sudden death have been reported in patients with concomitant use of methadone.

Drug Interactions

Concomitant use of certain drugs with itraconazole may lead to changes in the effectiveness of itraconazole and/or concomitantly used drugs, the 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 the “Drug Interactions” section.

Cross-hypersensitivity

Data regarding the presence of cross-hypersensitivity between itraconazole and other antifungal agents with an azole structure (from the azole group) are limited. If there is hypersensitivity to other azoles, Itraconazole should be prescribed with caution.

Reduced gastric acidity

With reduced gastric acidity, the absorption of itraconazole from capsules is impaired. Patients with reduced gastric acidity due to disease (e.g., in patients with achlorhydria) or due to medication (e.g., drugs that suppress gastric secretion) are recommended to take Canditral^® capsules simultaneously with acidic drinks (such as non-diet cola). The antifungal activity of the drug should be monitored and the dose of itraconazole should be increased if necessary.

Effect on liver function

In very rare cases, severe toxic liver damage, including several cases of acute liver failure with fatal outcome, developed during the use of Canditral^®. In most cases, this occurred in patients who already had liver disease, in patients with other serious diseases for whom the drug was prescribed for the treatment of systemic diseases, as well as in patients receiving other drugs with hepatotoxic effects. However, some patients had no concomitant diseases 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. If symptoms suggesting the occurrence of hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and dark urine, appear, treatment should be stopped immediately and liver function tests should be performed. Patients with elevated liver enzyme activity or active liver disease, or with a history of toxic liver damage due to other drugs should not be prescribed treatment with Canditral^®, except in cases where the expected benefit justifies the risk of liver damage. In such cases, liver enzyme activity should be monitored during treatment. Itraconazole is predominantly metabolized in the liver. Since in patients with impaired liver function the terminal T_1/2 of itraconazole is somewhat prolonged, it is recommended to monitor plasma concentrations of itraconazole and, if necessary, adjust the drug dose.

Impaired renal function

Data on the use of the drug in patients with impaired renal function are limited; in some patients with renal insufficiency, the exposure to itraconazole may be reduced. Therefore, the drug should be prescribed with caution to such patients. It is recommended to monitor plasma concentrations of itraconazole and, if necessary, adjust the drug dose.

Immunocompromised patients

The bioavailability of orally administered itraconazole may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, AIDS patients or those who have undergone organ transplantation.

Patients with life-threatening systemic fungal infections

Due to the pharmacokinetic characteristics of Canditral^® in capsule form, its use is not recommended for the initiation of treatment of systemic mycoses that are life-threatening to patients.

AIDS patients

The attending physician should assess the need for maintenance therapy in AIDS patients who have previously been treated for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (both meningeal and non-meningeal), who are at risk of relapse.

Hearing loss

Temporary or permanent hearing loss has been reported in patients taking Itraconazole. In some cases, hearing loss occurred against the background of concomitant use with quinidine (see sections “Contraindications” and “Drug Interactions”). Hearing usually recovers after the end of therapy with Canditral^®, but in some patients, hearing loss is irreversible.

Fertility

Animal studies have not shown reproductive toxicity for itraconazole.

Use in Pediatric Practice

Since clinical data on the use of Canditral^® in children are insufficient, the drug should be prescribed to children only if the potential benefit of treatment outweighs the potential risk.

Other

Women of childbearing potential taking Canditral^® must use adequate methods of contraception throughout the course of treatment until the first menstruation after its completion.

Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Canditral^® capsules.

For systemic candidiasis presumably caused by fluconazole-resistant strains of Candida, susceptibility to itraconazole cannot be assumed; therefore, it is recommended to check susceptibility before starting itraconazole therapy.

Effect on Ability to Drive Vehicles and Operate Machinery
Studies on the effect of Canditral^® on the ability to drive vehicles and operate machinery have not been conducted. The possibility of adverse reactions such as dizziness, visual disturbances, and hearing loss should be taken into account (see “Adverse Reactions”). If the described undesirable effects occur, one should refrain from performing these activities.

Overdose

Symptoms observed with an overdose of Canditral^® capsules were comparable to dose-dependent adverse reactions observed with the use of conventional doses of the drug.

Treatment There is no specific antidote. In case of overdose, supportive therapy, gastric lavage with a sodium bicarbonate solution, and administration of activated charcoal are performed. Itraconazole is not removed from the body by hemodialysis.

Drug Interactions

Itraconazole is predominantly metabolized by the CYP3A4 isoenzyme. Other drugs that are also metabolized by this isoenzyme or alter its activity may affect the pharmacokinetics of itraconazole. Similarly, Itraconazole may affect the pharmacokinetics of drugs that are also metabolized by this isoenzyme. Itraconazole is a strong inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. When itraconazole is used concomitantly with other drugs, it is recommended to consult the prescribing information to determine the drug’s metabolism pathway and to decide on the need for dose adjustment.

Drugs that may decrease the plasma concentration of itraconazole

Drugs that reduce gastric acidity (for example, antacids such as aluminum hydroxide, or agents that suppress hydrochloric acid secretion, such as H₂-receptor antagonists and proton pump inhibitors) impair the absorption of Canditral^® capsules. These drugs should be used with caution in combination with Canditral^® capsules

• Itraconazole is recommended to be taken with acidic beverages (such as non-diet cola) when used concomitantly with drugs that reduce gastric acidity.
• Drugs that neutralize hydrochloric acid (e.g., aluminum hydroxide) should be taken at least 1 hour before or 2 hours after taking Canditral^® capsules.
• When drugs are used concomitantly, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Concomitant use of itraconazole with strong inducers of the CYP3A4 isoenzyme may reduce the bioavailability of itraconazole and hydroxyitraconazole to such an extent that the efficacy of the drug is reduced. Examples include the following drugs

• Antibacterial agents – isoniazid, rifabutin, rifampicin;
• Anticonvulsants – carbamazepine, phenobarbital, phenytoin;
• Antiviral drugs – efavirenz, nevirapine.

Therefore, the use of strong inducers of the CYP3A4 isoenzyme concomitantly with itraconazole is not recommended. It is recommended to avoid prescribing these drugs for 2 weeks before starting itraconazole and during treatment with the drug, except when the expected benefit outweighs the potential risk associated with reduced efficacy of itraconazole. When drugs are used concomitantly, it is recommended to monitor the antifungal activity of itraconazole and increase the dose of the drug if necessary.

Drugs that may cause an increase in the plasma concentration of itraconazole

Concomitant administration of itraconazole and strong inhibitors of the CYP3A4 isoenzyme may lead to an increase in the bioavailability of itraconazole. Examples of strong inhibitors of the CYP3A4 isoenzyme

• Antibacterial drugs – ciprofloxacin, clarithromycin, erythromycin;
• Antiviral agents – darunavir boosted with ritonavir, fosamprenavir boosted with ritonavir, indinavir, ritonavir and telaprevir.

These drugs should be used with caution concomitantly with itraconazole. It is recommended to carefully monitor patients taking Itraconazole concomitantly with strong inhibitors of the CYP3A4 isoenzyme for the timely detection of symptoms and signs of enhancement or prolongation of the pharmacological effects of itraconazole; if necessary, the dose of itraconazole may be reduced. If possible, it is recommended to monitor the plasma concentration of itraconazole.

Drugs whose plasma concentration may increase when used concomitantly with itraconazole

Itraconazole and its main metabolite hydroxyitraconazole may impair the metabolism of drugs metabolized by the CYP3A4 isoenzyme and interfere with drug transport mediated by P-glycoprotein. This may lead to an increase in the plasma concentration of these drugs and/or their active metabolites when taken concomitantly with itraconazole. The increase in plasma concentration, in turn, may cause enhancement or prolongation of both therapeutic and adverse effects of these drugs, potentially leading to life-threatening conditions. For example, an increase in the concentration of some drugs (terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, quinidine, pimozide, sertindole, levomethadone) may lead to QT interval prolongation and ventricular tachyarrhythmia, including cases of torsades de pointes, which is a potentially life-threatening condition. After discontinuation of treatment, the plasma concentration of itraconazole decreases to virtually undetectable levels within 7 to 14 days, depending on the dose of the drug and the duration of treatment. In patients with liver cirrhosis or those concomitantly taking CYP3A4 enzyme inhibitors, the decrease in drug concentration may be even slower. This is particularly important when initiating therapy with drugs whose metabolism is affected by Itraconazole.

Interacting drugs are divided into the following categories:

• “Contraindicated”: Under no circumstances should this drug be used in combination with itraconazole and for 2 weeks after discontinuation of itraconazole.
• “Not recommended”: It is recommended to avoid the use of this drug during treatment and for 2 weeks after discontinuation of itraconazole, except when the expected benefit outweighs the potential risk associated with the therapy. If the use of this drug combination cannot be avoided, it is recommended to monitor the patient for the timely detection of symptoms and signs of enhancement or prolongation of drug effects or development of side effects; if necessary, treatment can be interrupted or the dose of the drugs reduced. If possible, it is recommended to monitor the plasma concentration of the drugs.
• “Use with caution”: Careful monitoring should be carried out when the drug is used concomitantly with itraconazole. When drugs are used concomitantly, it is recommended to monitor the patient for the timely detection of symptoms and signs of enhancement or prolongation of drug effects or development of side effects; if necessary, treatment can be interrupted or the dose of the drugs reduced. If possible, it is recommended to monitor the plasma concentration of the drugs.

Below are examples of drugs whose plasma concentration may increase under the influence of itraconazole. The drugs are divided by class, and recommendations for concomitant use with itraconazole are also given.

^a See also section “Drugs that may decrease the plasma concentration of itraconazole”.

^b See also section “Drugs that may increase the plasma concentration of itraconazole”.

Drugs whose plasma concentration may decrease under the influence of itraconazole

Concomitant use of itraconazole with the NSAID meloxicam may reduce the plasma concentration of meloxicam. It is recommended to prescribe meloxicam concomitantly with itraconazole with caution and to carefully monitor the patient’s clinical condition and the occurrence of side effects. If necessary, the dose of meloxicam should be adjusted.

Children

Drug interactions have been studied only in adults.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years 6 months. 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.