Eszol

Itraconazole.

Each film coated tablet contains: Itraconazole BP 100 mg.
Excipients/Inactive Ingredients: Sugar pellets, microcrystalline cellulose, hydroxyl propyl methyl cellulose, lactose pharmatose, sodium starch glycolate, croscarmellose sodium, low substituted hydroxyl propyl cellulose, povidone K-30, magnesium stearate, colloidal anhydrous silica, opadry II pink, purified water, dichloromethane and isopropyl alcohol.

Pharmacotherapeutic group: Antifungal. ATC CODE: J02AC02.
Pharmacology: Pharmacodynamics: Eszol contains Itraconazole which is a triazole derivative, has a broad spectrum of activity.
In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
For itraconazole, breakpoints have only been established for Candida spp. From superficial mycotic infections (CLSI M27-A2, breakpoints have not been established for EUCAST methodology). The CLSI breakpoints are as follows: susceptible ≤0.125; susceptible, dose-dependent 0.25-0.5 and resistant ≥1μg/mL. Interpretive breakpoints have not been established for the filamentous fungi.
In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤1μg/ml. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp.; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidiodes immitis; Pseudallescheria boydii; Penicillium marneffei; and various other yeasts and fungi.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.
Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Pharmacokinetics: Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with C_max values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption: Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the tablets are taken immediately after a full meal.
Absorption of itraconazole tablets is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H₂-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see Precautions, and Interactions). Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole tablet are administered with an acidic beverage (such as a non-diet cola). When itraconazole tablet were administered as a single 200 mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H₂-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole tablet were administered alone. (See Interactions). Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See Precautions).
Distribution: Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma and uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.
Metabolism: Itraconazole is extensively metabolised by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Trough Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.
Elimination: Itraconazole is excreted mainly as inactive metabolites in urine (35%) and faeces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabelled dose, faecal excretion of unchanged drug varies between 3 - 18% of the dose.
Special populations: Hepatic impairment: Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg tablet) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC (missing) were seen between these two groups. A statistically significant reduction in average C_max (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects.
Data are not available in cirrhotic patients during long-term use of itraconazole. (See Dosage & Administration, and Precautions).
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg tablets) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 ml/min. × 1.73 m², the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (T_max, C_max, and AUC_0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects, (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively.). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See also Dosage & Administration, and Precautions).
Paediatrics: Limited pharmacokinetic data are available on the use of itraconazole in the paediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole tablets, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, C_max and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.

Eszol is indicated for: Vulvovaginal candidosis; Pityriasis versicolor; Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum; Oropharyngeal candidosis; Onychomycosis caused by dermatophytes and/or yeasts; The treatment of histoplasmosis.
Eszol is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity: Treatment of aspergillosis and candidosis.
Treatment of cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system.
Maintenance therapy in AIDS patients to prevent relapse of underlying fungal infection.
Eszol is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.

Treatment schedules in adults are given as follows: Indication: Vulvovaginal candidosis.
Dose¹: 200 mg twice daily for 1 day.
Indication: Pityriasis versicolor.
Dose¹: 200 mg once daily for 7 days.
Indication: Tinea corporis, tinea cruris.
Dose¹: 100 mg once daily for 15 days or 200 mg once daily for 7 days.
Indication: Tinea pedis, tinea manuum.
Dose¹: 100 mg once daily for 30 days.
Indication: Oropharyngeal candidosis.
Dose¹: 100 mg once daily for 15 days.
Remarks: Increase dose to 200 mg once daily for 15 days in AIDS or neutropenic patients because of impaired absorption in these groups.
Indication: Onychomycosis (toenails with or without fingernail involvement).
Dose¹: 200 mg once daily for 3 months.
For skin, vulvovaginal and oropharyngeal infections, optimal clinical and mycological effects are reached 1 - 4 weeks after cessation of treatment and for nail infections, 6 - 9 months after the cessation of treatment. This is because elimination of itraconazole from skin, nails and mucous membranes is slower than from plasma.
The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy: Indication: Aspergillosis.
Dose¹: 200 mg once daily.
Remarks: Increase dose to 200 mg twice daily in case of invasive or disseminated disease.
Indication: Candidosis.
Dose¹: 100-200 mg once daily.
Remarks: Increase dose to 200 mg twice daily in case of invasive or disseminated disease.
Indication: Non-meningeal Cryptococcosis.
Dose¹: 200 mg once daily.
Indication: Cryptococcal meningitis.
Dose¹: 200 mg twice daily.
Remarks: See Precautions.
Indication: Histoplasmosis.
Dose¹: 200 mg once daily-200 mg twice daily.
Indication: Maintenance in AIDS.
Dose¹: 200 mg once daily.
Remarks: See note on impaired absorption as follows.
Indication: Prophylaxis in neutropenia.
Dose¹: 200 mg once daily.
Remarks: See note on impaired absorption as follows.
¹The duration of treatment should be adjusted depending on the clinical response.
Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases, blood level monitoring and if necessary, an increase in itraconazole dose to 200 mg twice daily, is indicated.
Special population: Paediatrics: Clinical data on the use of Eszol in paediatric patients are limited. The use of Eszol in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks. See Precautions.
Elderly: Clinical data on the use of Eszol in elderly patients are limited. It is advised to use Eszol in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. See Precautions.
Renal impairment: The oral bioavailability of itraconazole may be lower in patients with renal insufficiency, a dose adjustment may be considered. See Precautions.
Hepatic impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See Pharmacology: Pharmacokinetics: Special populations: Hepatic impairment under Actions).
Mode of administration: Eszol is for oral administration and must be taken immediately after a meal for maximal absorption.

No data are available.
In the event of overdosage, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Eszol is contra-indicated in patients with known hypersensitivity to itraconazole or to any of the excipients.
Coadministration of the following drugs is contraindicated with Eszol: CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Eszol. Coadministration may result in increased plasma concentrations of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes; CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin; Triazolam and oral midazolam; Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine); Eletriptan; Nisoldipine; Eszol should not be administered for non-life threatening indications to patients receiving disopyramide or halofantrine.
Eszol should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. See Precautions. Eszol must not be used during pregnancy for non-life-threatening indications (see Use in Pregnancy & Lactation).
Women of childbearing potential taking Eszol should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Eszol therapy.

Cross-hypersensitivity: There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Eszol to patients with hypersensitivity to other azoles.
Cardiac effects: In a healthy volunteer study with itraconazole, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. The clinical relevance of these findings to the oral formulations is unknown.
Itraconazole has been shown to have a negative inotropic effect and Itraconazole tablets have been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.
Itraconazole should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dose and duration of treatment (e.g. total daily dose), and individual risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, Eszol should be discontinued.
Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when co-administering itraconazole and calcium channel blockers (see Interactions) due to an increased risk of congestive heart failure.
Hepatic effects: Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Itraconazole. Most of these cases involved patients who, had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Eszol treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine.
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolised by CYP3A4.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See Pharmacology: Pharmacokinetics: Special populations: Hepatic impairment under Actions).
Reduced gastric acidity: Absorption of itraconazole from Eszol is impaired when gastric acidity is reduced. In patients also receiving acid neutralising medicines (e.g. aluminium hydroxide), these should be administered at least 2 hours after the intake of Eszol. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H₂-antagonists, proton-pump inhibitors), it is advisable to administer Eszol with a cola beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. See Interactions.
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.
Hearing loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Immunocompromised patients: In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Eszol may be decreased.
Patients with immediately life-threatening systemic fungal infections: Due to the pharmacokinetic properties, itraconazole tablets are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.
Patients with AIDS: In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.
Neuropathy: If neuropathy occurs which may be attributable to itraconazole, the treatment should be discontinued.
Disorders of carbohydrate metabolism: Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Cross-resistance: In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of Eszol therapy.
Interaction potential: Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in section Interactions with other medicinal products.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (see Adverse Reactions), which may occur in some instances, must be taken into account.
Use in Children: Clinical data on the use of Eszol in paediatric patients is limited. Eszol should not be used in paediatric patients unless the potential benefit outweighs the potential risks.
Use in the Elderly: Clinical data on the use of itraconazole in elderly patients are limited. It is advised to use itraconazole in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pregnancy: Eszol must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus see Contraindications.
In animal studies itraconazole has shown reproduction toxicity see Contraindications.
There is limited information on the use of Eszol during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with itraconazole has not been established.
Epidemiological data on exposure to itraconazole during the first trimester of pregnancy-mostly in patients receiving short-term treatment for vulvovaginal candidosis-did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.
Women of child bearing potential: Women of childbearing potential taking Eszol should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Eszol therapy..
Lactation: A very small amount of itraconazole is excreted in human milk. The expected benefits of Eszol therapy should be weighed against the risks of breast feeding. In case of doubt, the patient should not breast feed.

Undesirable effects listed as follows have been reported in clinical trials with itraconazole tablets and/or from spontaneous reports from post-marketing experience for all itraconazole formulations.
The table as follows presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention: Very common (>1/10); Common (>1/100 to < 1/10); Uncommon (>1/1,000 to < 1/100); Rare (>1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
Infections and infestations: Uncommon: Sinusitis, Upper respiratory tract infection, Rhinitis.
Blood and lymphatic system disorders: Rare: Leukopenia.
Immune system disorders: Rare: Anaphylactic Reaction, Angioneurotic Oedema and Serum Sickness.
Uncommon: Hypersensitivity*.
Metabolism and nutrition disorders: Not known: Hypertriglyceridemia.
Nervous system disorders: Common: Headache.
Rare: Hypoaesthesia, Paraesthesia, Dysgeusia.
Eye disorders: Rare: Visual Disturbance (Vision Blurred and Diplopia).
Ear and labyrinth disorder: Rare: Transient or permanent Hearing Loss*, Tinnitus.
Cardiac disorders: Rare: Congestive Heart Failure*.
Respiratory, thoracic and mediastinal disorders: Rare: Dyspnoea.
Gastrointestinal disorders: Common: Abdominal Pain, Nausea.
Uncommon: Vomiting, Diarrhoea, Constipation, Dyspepsia, Flatulence.
Rare: Pancreatitis.
Hepatobiliary disorders: Uncommon: Hepatic function abnormal.
Rare: Serious hepatotoxicity (including some cases of fatal acute liver failure)*, Hyperbilirubinaemia.
Skin and subcutaneous tissue disorders: Uncommon: Urticaria, Alopecia, Pruritus.
Rare: Toxic Epidermal Necrolysis, Stevens - Johnson syndrome, Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis, Photosensitivity.
Renal and urinary disorders: Rare: Pollakiuria.
Reproductive system and breast disorders: Uncommon: Menstrual disorder.
Rare: Erectile Dysfunction.
General disorders and administration site conditions: Rare: Oedema.
Investigations: Rare: Blood creatine phosphokinase increased.
Description of selected adverse reactions: The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of Itraconazole Oral Solution and Itraconazole I.V., excluding the ADR term 'Injection site inflammation', which is specific to the injection route of administration.
Blood and lymphatic system disorders: Granulocytopenia, Thrombocytopenia.
Immune system disorders: Anaphylactoid reaction.
Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypokalaemia, Hypomagnesaemia.
Psychiatric disorders: Confusional state.
Nervous system disorders: Peripheral neuropathy*, Dizziness, Somnolence, Tremor.
Cardiac disorders: Cardiac failure, Left ventricular failure, Tachycardia.
Vascular disorders: Hypertension, Hypotension.
Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia, Cough.
Gastrointestinal disorders: Gastrointestinal disorder.
Hepatobiliary disorders: Hepatic failure*, Hepatitis, Jaundice.
Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis.
Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia.
Renal and urinary disorders: Renal impairment, Urinary incontinence.
General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pyrexia, Pain, Fatigue, Chills,
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal.
Paediatric population: The safety of Itraconazole tablets was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a double-blind phase). These patients received at least one dose of Itraconazole tablets for the treatment of fungal infections and provided safety data.
Based on pooled safety data from these clinical trials, the commonly reported adverse drug reactions (ADRs) in paediatric patients were Headache (3.0%), Vomiting (3.0%), Abdominal pain (2.4%), Diarrhoea (2.4%), Hepatic function abnormal (1.2%), Hypotension (1.2%), Nausea (1.2%), and Urticaria (1.2%). In general, the nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.
Adverse Drug Reactions: Inform doctors about unexpected reactions after using drugs.

Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.
Drugs that may decrease itraconazole plasma concentrations: Drugs that reduce the gastric acidity (e.g. acid neutralising medicines such as aluminum hydroxide, or acid secretion suppressors such as H₂-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole tablets. It is recommended that these drugs be used with caution when coadministered with itraconazole tablets: It is recommended that itraconazole be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
It is recommended that acid neutralising medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of Eszol tablets.
Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be largely reduced. Examples include: Antibacterials: isoniazid, rifabutin (see also under Drugs that may have their plasma concentrations increased by itraconazole), rifampicin.
Anticonvulsants: carbamazepine, (see also under Drugs that may have their plasma concentrations increased by itraconazole as follows), phenobarbital, phenytoin.
Antivirals: efavirenz, nevirapine.
Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
Drugs that may increase itraconazole plasma concentrations: Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include: Antibacterials: Ciprofloxacin, clarithromycin, erythromycin,
Antivirals: Ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under Drugs that may have their plasma concentrations increased by itraconazole), ritonavir (see also under Drugs that may have their plasma concentrations increased by itraconazole as follows).
It is recommended that these drugs be used with caution when coadministered with itraconazole tablets. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.
Drugs that may have their plasma concentrations increased by itraconazole: Itraconazole and its major metabolite, hydroxyitraconazole, can inhibit the metabolism of drugs metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolised drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
The interacting drugs are categorized as follows: 'Contraindicated': Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.
'Not recommended': It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.
'Use with caution': Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.
Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole: See table.

Click on icon to see table/diagram/image

Drugs that may have their plasma concentrations decreased by itraconazole: Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentrations of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adapted if necessary.
Paediatric Population: Interaction studies have only been performed in adults.

Store below 30°C.
Shelf-Life: 36 months.

Antifungals

J02AC02 - itraconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

POM

FC tab 100 mg (pink colored, capsule shaped, 'ITR 100' embossed on one side and plain on other side) x 1 x 10's.