Micotenk

Overdose

Symptoms:

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for Micotenk.

Treatment:

In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Micotenk cannot be removed by haemodialysis. No specific antidote is available.

Symptoms and signs

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.

Micotenk price

Contraindications

Micotenk oral solution is contraindicated in patients with a known hypersensitivity to Micotenk or to any of the excipients.

Co-administration of the following drugs is contraindicated with Micotenk oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

- 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 Micotenk oral solution.).

- Women of childbearing potential taking Micotenk Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Micotenk Capsules therapy.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Not applicable.

Undesirable effects

Approximately 9% of patients can be expected to experience adverse reactions while taking Micotenk. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.

The table below 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).

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) with Micotenk 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 Micotenk 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).

Description of selected adverse reactions

The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of Micotenk Oral Solution and Micotenk 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 Micotenk 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 Micotenk 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.

Preclinical safety data

Epidemiological data on exposure to Micotenk 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 Micotenk oral solution should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Micotenk therapy.

Fertility:

In the rat, Micotenk had no effect on male or female fertility at doses which exhibited signs of general toxicity. The effect in humans is unknown.

Lactation:

A very small amount of Micotenk is excreted in human milk. Micotenk Oral Solution must not be used during lactation.

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.

Approximately 9% of patients can be expected to experience adverse reactions while taking Micotenk. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.

The table below 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).

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.

Therapeutic indications

Micotenk oral solution is indicated:

- For the treatment of oral and/or oesophageal candidosis in HIV-positive or other immunocompromised patients.

- As prophylaxis of deep fungal infections anticipated to be susceptible to Micotenk, when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e. < 500 cells/µl). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

Micotenk oral solution is indicated for use in adults.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

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. Micotenk 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.

Micotenk is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

ATC code: J02A C02

Mode of action

Micotenk inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.

PK/PD relationship

The PK/PD relationship for Micotenk, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.

Mechanism(s) of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are

- Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)

- Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for Micotenk

- Drug-transporter over-expression resulting in increased efflux of Micotenk from fungal cells (i.e., removal of Micotenk from its target)

- Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles.

Breakpoints

Breakpoints for candida species are in preparation.

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

The in vitro susceptibility of fungi to Micotenk depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of Micotenk may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Micotenk/L. There is no correlation between in vitro susceptibility and clinical efficacy.

1 These organisms may be encountered in patients who have returned from travel outside Europe.

2 Micotenk-resistant strains of Aspergillus fumigatus have been reported.

3 Natural intermediate susceptibility.

Paediatric Population

The tolerability and safety of Micotenk oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of Micotenk oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to Micotenk were vomiting, abnormal liver function, and abdominal pain.

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.

Pharmacokinetic properties

Use in patients with renal impairment

Limited data are available on the use of oral Micotenk in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Micotenk oral solution is contraindicated in patients with a known hypersensitivity to Micotenk or to any of the excipients.

Co-administration of the following drugs is contraindicated with Micotenk oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

- 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 Micotenk oral solution.).

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between Micotenk and other azole antifungal agents. Caution should be used in prescribing Micotenk Oral Solution to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Micotenk IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

Micotenk has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Micotenk. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Micotenk 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. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity 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. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Micotenk.

Use in children

Since clinical data on the use of Micotenk oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of Micotenk oral solution in elderly patients is limited, it is advised to use Micotenk oral solution in these patients only if the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral Micotenk in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Renal impairment

Limited data are available on the use of oral Micotenk in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Prophylaxis in neutropenic patients

In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Micotenk oral solution in these circumstances.

Treatment of severely neutropenic patients

Micotenk oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Micotenk oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with Micotenk. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Neuropathy

If neuropathy occurs that may be attributable to Micotenk oral solution, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Micotenk, hence their sensitivity should be tested before the start of Micotenk therapy

Interaction potential

Micotenk Oral Solution has a potential for clinically important drug interactions.

Micotenk should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Micotenk with these drugs may lead to subtherapeutic plasma levels of Micotenk and thus treatment failure.

Micotenk oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.

4.5.1. Drugs affecting the metabolism of Micotenk:

Micotenk is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of Micotenk and hydroxy-Micotenk was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of Micotenk with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated.

Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of Micotenk.

4.5.2. Effect of Micotenk on the metabolism of other drugs:

4.5.2.1 Micotenk can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of Micotenk on co-medicated drugs is considered.

The following drugs are contraindicated with Micotenk:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Micotenk oral solution since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

- CYP3A4 metabolized 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

Caution should be exercised when co-administering Micotenk with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of Micotenk.

The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with Micotenk, should be reduced if necessary:

- Oral anticoagulants;

- HIV protease inhibitors such as ritonavir, indinavir, saquinavir;

- Certain antineoplastic agents such as busulfan, docetaxel, trimetrexate and vinca alkaloids;

- CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;

- Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as sirolimus);

- Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;

- Digoxin (via inhibition of P-glycoprotein)

- Others: cilostazol, disopyramide, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, repaglinide, fentanyl, halofantrine, reboxetine and loperamide. The importance of the concentration increase and the clinical relevance of these changes during the co-administration with Micotenk remain to be established.

4.5.2.2 No interaction of Micotenk with zidovudine (AZT) and fluvastatin has been observed.

No inducing effects of Micotenk on the metabolism of ethinyloestradiol and norethisterone were observed.

4.5.3. Effect on protein binding:

In vitro studies have shown that there are no interactions on the plasma protein binding between Micotenk and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.

Pregnancy:

Micotenk oral solution 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 4.3 Contraindications).

In animal studies Micotenk has shown reproduction toxicity (see

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

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

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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between Micotenk and other azole antifungal agents. Caution should be used in prescribing Micotenk Oral Solution to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Micotenk IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

Micotenk has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Micotenk. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Micotenk 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. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity 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. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Micotenk.

Use in children

Since clinical data on the use of Micotenk oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of Micotenk oral solution in elderly patients is limited, it is advised to use Micotenk oral solution in these patients only if the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral Micotenk in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Renal impairment

Limited data are available on the use of oral Micotenk in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Prophylaxis in neutropenic patients

In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Micotenk oral solution in these circumstances.

Treatment of severely neutropenic patients

Micotenk oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Micotenk oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with Micotenk. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Neuropathy

If neuropathy occurs that may be attributable to Micotenk oral solution, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Micotenk, hence their sensitivity should be tested before the start of Micotenk therapy

Interaction potential

Micotenk Oral Solution has a potential for clinically important drug interactions.

Micotenk should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Micotenk with these drugs may lead to subtherapeutic plasma levels of Micotenk and thus treatment failure.

Micotenk oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.

Elderly

Clinical data on the use of Micotenk 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)

- Women of childbearing potential taking Micotenk Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Micotenk Capsules therapy.

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Micotenk Capsules to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Micotenk® 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 Micotenk Capsules.Pharmacokinetic properties - Special Populations, Hepatic impairment.)

Reduced gastric acidity

Absorption of itraconazole from Micotenk 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 Micotenk Capsules in paediatric patients is limited. The use of Micotenk 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 Micotenk Capsules in elderly patients are limited. It is advised to use Micotenk 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 Micotenk Capsules may be decreased.

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 Micotenk 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 Micotenk therapy.

Interchangeability

It is not recommended that Micotenk Capsules and Micotenk 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.

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 , which may occur in some instances, must be taken into account.

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.

Dosage (Posology) and method of administration

For optimal absorption, Micotenk oral solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).

A graduated measuring cup is provided to measure out the correct dose.

For the treatment of oral and/or oesophageal candidosis, the liquid should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.

Treatment of oral and/or oesophageal candidosis: 200 mg (20 ml) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or oesophageal candidosis: 100 to 200 mg (10-20 ml) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement.

Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100 cells/µl. Treatment was continued until recovery of neutrophils (i.e. > 1000 cells/µl).

Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Micotenk oral solution.

Use in children

Since clinical data on the use of Micotenk oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes.

Use in elderly

Since clinical data on the use of Micotenk oral solution in elderly patients is limited, it is advised to use Micotenk oral solution in these patients only if the potential benefit outweighs the potential risks.

Use in patients with hepatic impairment

Limited data are available on the use of oral Micotenk in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Use in patients with renal impairment

Limited data are available on the use of oral Micotenk in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Micotenk 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:

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:

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 Micotenk Capsules in paediatric patients are limited.Special warnings and precautions for use.

Elderly

Clinical data on the use of Micotenk 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)

Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

No special requirements.