Symptoms and signs
Undesirable effects)Treatment
In the event of overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.
- Women of childbearing potential taking Itraconazol Mylan Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itraconazol Mylan Capsules therapy.
Not applicable.
Summary of the safety profile
The most frequently reported adverse drug reactions (ADRs) with Itraconazol Mylan Capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea.Special warnings and precautions for use for additional information on other serious effects.
Tabulated list of adverse reactions
The ADRs in the table below were derived from open-label and double-blind clinical trials with Itraconazol Mylan Capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, and from spontaneous reporting.
The table below presents ADRs by System Organ Class. Within each System Organ Class, the ADRs 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).
| Adverse Drug Reactions | |
| Infections and infestations | |
| Uncommon | Sinusitis, Upper respiratory tract infection, Rhinitis |
| Blood and lymphatic system disorders | |
| Rare | Leukopenia |
| Immune system disorders | |
| Uncommon | Hypersensitivity* |
| Rare | Serum sickness, Angioneurotic oedema, Anaphylactic reaction |
| Metabolism and nutrition disorders | |
| Rare | Hypertriglyceridaemia |
| Nervous system disorders | |
| Common | Headache |
| Rare | Paraesthesia, Hypoaesthesia, Dysgeusia |
| Eye disorders | |
| Rare | Visual disturbance (including diplopia and blurred vision) |
| 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 | Diarrhoea, Vomiting, 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, Rash, Pruritus |
| Rare | Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalised exanthematous pustulosis, Erythema multiforme, Exfoliative dermatitis, Leukocytoclastic vasculitis, Alopecia, 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 Itraconazol Mylan Oral Solution and Itraconazol Mylan I.V., excluding the ADR term “Injection site inflammationâ€, 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 Itraconazol Mylan Capsules 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 Itraconazol Mylan Capsules 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.
Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.
1. Vulvovaginal candidosis.
2. Pityriasis versicolor.
3. Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum.
4. Oropharyngeal candidosis.
5. Onychomycosis caused by dermatophytes and/or yeasts.
6. The treatment of histoplasmosis.
7. Itraconazol Mylan 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. |
Itraconazol Mylan is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.
Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole derivatives).
ATC code: J02A C02
Itraconazole, 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 ≤ 1 µg/ml. These include:
dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including H. capsulatum; 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.
General pharmacokinetic characteristics
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 Cmax 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
Interactions).Special Warnings and Precautions for use.)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 the 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.
Excretion
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
Special warnings and precautions for use.)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 capsules, 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, Cmax and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.
Elderly
Clinical data on the use of Itraconazol Mylan Capsules in elderly patients are limited.Special warnings and precautions for use.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)
4.3 Contraindications Fertility, pregnancy and lactation)- Women of childbearing potential taking Itraconazol Mylan Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itraconazol Mylan Capsules therapy.
4.4 Special warnings and precautions for useCross-hypersensitivity
There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Itraconazol Mylan Capsules to patients with hypersensitivity to other azoles.
Cardiac effects
In a healthy volunteer study with Itraconazol Mylan® IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion.Interaction with other medicinal products and other forms of interaction) 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 Itraconazol Mylan Capsules.Pharmacokinetic properties - Special Populations, Hepatic impairment.)
Reduced gastric acidity
Absorption of itraconazole from Itraconazol Mylan Capsules is impaired when gastric acidity is reduced. Interaction with other medicinal products and other forms of interaction.
Paediatrics
Clinical data on the use of Itraconazol Mylan Capsules in paediatric patients is limited. The use of Itraconazol Mylan Capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Elderly
Clinical data on the use of Itraconazol Mylan Capsules in elderly patients are limited. It is advised to use Itraconazol Mylan Capsules 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.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Interaction with other medicinal products and other forms of interaction). 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 Itraconazol Mylan Capsules may be decreased.
Patients with immediately life-threatening systemic fungal infections
Pharmacokinetic properties), Itraconazol Mylan Capsules 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 Itraconazol Mylan Capsules, 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 Itraconazol Mylan therapy.
Interchangeability
It is not recommended that Itraconazol Mylan Capsules and Itraconazol Mylan Oral Solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.
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.Interaction with other medicinal products and other forms of interaction.
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 , which may occur in some instances, must be taken into account.
Itraconazol Mylan is for oral administration and must be taken immediately after a meal for maximal absorption. The capsules must be swallowed whole.
Treatment schedules in adults for each indication are as follows:
| Indication | Dose | Remarks |
| Vulvovaginal candidosis | 200 mg twice daily for 1 day | |
| Pityriasis versicolor | 200 mg once daily for 7 days | |
| Tinea corporis, tinea cruris | 100 mg once daily for 15 days or 200 mg once daily for 7 days | |
| Tinea pedis, tinea manuum | 100 mg once daily for 30 days | |
| Oropharyngeal candidosis | 100 mg once daily for 15 days | Increase dose to 200 mg once daily for 15 days in AIDS or neutropenic patients because of impaired absorption in these groups. |
| Onychomycosis (toenails with or without fingernail involvement) | 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 | Dose1 | Remarks |
| Aspergillosis | 200 mg once daily | Increase dose to 200 mg twice daily in case of invasive or disseminated disease |
| Candidosis | 100-200 mg once daily | Increase dose to 200 mg twice daily in case of invasive or disseminated disease |
| Non-meningeal Cryptococcosis | 200 mg once daily | |
| Cryptococcal meningitis | 200 mg twice daily | See 4.4. Special warnings and special precautions for use. |
| Histoplasmosis | 200 mg once daily - 200 mg twice daily | |
| Maintenance in AIDS | 200 mg once daily | See note on impaired absorption below |
| Prophylaxis in neutropenia | 200 mg once daily | See note on impaired absorption below |
1 The 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 populations
Paediatrics
Clinical data on the use of Itraconazol Mylan Capsules in paediatric patients are limited.Special warnings and precautions for use.
Elderly
Clinical data on the use of Itraconazol Mylan Capsules in elderly patients are limited.Special warnings and precautions for use.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)
No special requirements.
