SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Itrakonazol Actavis 100 mg, hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule, hard contains 100 mg of itraconazole. Excipient with known effect: Each capsule, hard contains mg sucrose. For the full list of excipients, see section PHARMACEUTICAL FORM Capsule, hard No. 0 hard gelatine capsules, opaque green cap and body, containing yellowish-beige spherical microgranules. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Itraconazole is indicated for the treatment of the following fungal infections verified by direct microscopy and/or cultures where systemic treatment is considered necessary: Vulvovaginal candidiasis, oral candidiasis, pityriasis versicolor, dermatomycoses, onychomycoses (caused by dermatophytes and yeasts). Consideration should be given to official guidance on the appropriate use of antifungal agents. 4.2 Posology and method of administration /.../ capsules are for oral use The capsules should be taken immediately after meals The capsules should be swallowed whole. Adults: Vulvovaginal candidiasis: 200 mg in the morning and 200 mg in the evening for 1 day. Oral candidiasis: 100 mg once daily for 2 weeks. Pityriasis versicolor: 200 mg once daily for 1 week. Tinea corporis/cruris: 100 mg once daily for 2 weeks. Tinea pedis/manus: 100 mg twice daily for 4 weeks. 2

3 Onychomycoses: Pulse treatment: Toenails with or without infected fingernails: 200 mg twice daily for 7 days, followed by a treatment-free interval of 3 weeks, 3 times in total. Fingernails: 200 mg twice daily for 7 days, followed by a treatment-free interval of 3 weeks, 2 times in total. or: 200 mg once daily for 3 months. For treatment of special patient groups such as diabetes patients and patients with impaired immune systems, see section 4.4. For skin infections optimal clinical effects are reached at 1-4 weeks after cessation of treatment and for nail infections at 6-9 months after the cessation of treatment. This is because elimination of itraconazole from skin and nails is slower than from plasma. Use in children: Since clinical data on the use of itraconazole oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks (see section 4.4). 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 (see section 4.8). Use in the elderly: Since clinical data is limited, itraconazole should only be used in the elderly if the potential benefit is estimated to outweigh the potential risk. Impaired hepatic function: Itraconazole is mainly metabolised in the liver. The terminal half-life is somewhat prolonged and the bioavailability is somewhat lower in cirrhotic patients. A dose adjustment should be considered for these patients. Monitoring of plasma levels may be necessary (see section 4.4). Impaired renal function: The plasma level in patients with renal insufficiency may become sub-therapeutic. Experience is limited with respect to dose adjustment in these patients. Monitoring of plasma levels may be necessary. Itraconazole cannot be removed by dialysis. Decreased gastric acidity: Absorption of itraconazole is impaired when gastric acidity is decreased. For information on patients with achlorhydria and patients on acid secretion suppressors or taking acid neutralising medicinal products, see section 4.4. Patients with AIDS and neutropenia 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 dose adjustment might be indicated, see section Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section

4 Co-administration of the following drugs is contraindicated with itraconazole capsules (see section 4.5): - CYP3A4 metabolized substrates e.g. terfenadine, astemizole, mizolastine, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), pimozide, quinidine, sertindole are contraindicated with itraconazole capsules. 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 metabolised HMG-CoA reductase inhibitors, such as lovastatin, simvastatin and atorvastatin - Triazolam and oral midazolam - Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) - Eletriptan - Nisoldipine - Ranolazine - Dabigatran etexilate Itraconazole capsules 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 section 4.4). Itraconazole Actavis must not be used during pregnancy (except for life-threatening cases). See section 4.6. Women of childbearing potential taking Itraconazole Actavis should use contraceptive precautions. Effective contraception should be contionued until the menstrual period following the end of Itraconazole Actavis therapy. 4.4 Special warnings and precautions for use Cross-hypersensitivity There is no information regarding cross-hypersensitivity between itraconazole and other antimycotic azoles. Caution should be used in prescribing /.../ capsules to patients hypersensitive to other azoles. Cardiac effects In a healthy volunteer study of intravenous itraconazole, transient, asymptomatic decreases in left ventricular ejection fraction were 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 has 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. The individual risk-benefit assessment should consider factors such as the severity of the indication, the dosing regimen (e.g. total daily dose), the duration of treatment 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. Patients with these risk factors should be informed of the signs and symptoms of congestive heart failure. During treatment caution should be exercised and the patient monitored for the signs and symptoms of congestive heart failure. Itraconazole should be discontinued if such signs or symptoms occur during treatment. 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 used when co-administering itraconazole and CYP3A4 metabolized calcium channel blockers (such as dihydropyridines, verapamil and felodipine) (see section 4.5) due to an increased risk of CHF. 4

5 Hepatic effects Very rare cases of severe hepatotoxicity, including some cases of fatal acute liver failure, have been reported in patients treated with itraconazole. Some of these cases involved patients who had no preexisting 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 itraconazole. Patients should be instructed to promptly report to their physician any 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 severe 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 an active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit outweighs the risk of hepatic injury. In such cases, liver enzyme monitoring is necessary. Reduced gastric acidity Absorption of itraconazole is impaired when gastric acidity is decreased. In patients also receiving acid neutralising medicines (e.g. aluminium hydroxide) these should be administered at least 2 hours after the intake of itraconazole capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (e.g. H 2 -antagonists, proton-pump inhibitors) it is advisable to administer itraconazole with acid drink, such as cola beverage, since adequate absorption requires a low ph in the stomach. Use in children The effect of pulse therapy has not been studied in children. There is only little clinical experience of using itraconazole in children. Itraconazole capsules should therefore not be administered to children, except in cases where the expected positive effects outweigh the potential risks. Use in elderly Clinical data on the use of itraconazole capsules in elderly patients is limited. Itraconazole capsules should not be used in these patients unless the potential benefit outweighs the potential risks. Hepatic impairment 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 (see section 5.2). 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 sections 4.3 and 4.5). 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 itraconazole capsules may be decreased. Experience is limited with respect to pulse therapy of diabetes patients and patients with impaired immune systems (see section 5.2). Patients with immediately life-threatening systemic fungal infections Due to the pharmacokinetic properties (see section 5.2), itraconazole capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections. 5

6 Patients with AIDS In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal and 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, treatment should be discontinued. Disorders of Carbohydrate Metabolism /.../ contains sucrose. 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 itraconazole therapy. Interaction potential Itraconazole is a potent inhibitor of CYP3A4. Co-administration of itraconazole and medicinal products metabolised via CYP3A4 may result in markedly increased plasma levels of CYP3A4 substrates (see sections 4.3 and 4.5). Itraconazole should not be used during and two weeks after treatment with CYP3A4-inducing agents (such as rifampicin, rifabutin, phenytoin, phenobarbital, carbamazepine, St. John s Wort). Concomitant treatment with these medicinal products may result in sub-therapeutic levels of itraconazole and, thus, entail a risk of treatment failure (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicines on itraconazole: Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been conducted with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. The bioavailability of itraconazole and hydroxy-itraconazole in these studies was decreased to such an extent that efficacy may be largely reduced. The combination with enzyme inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, carbamazepine, isoniazid) is not recommended. Since similar effects are also to be expected with St. John s Wort (Hypericum Perforatum), concomitant use should be avoided (see section 4.4). Potent inhibitors of CYP3A4 such as ritonavir, indinavir, clarithromycin and erythromycin can increase the bioavailability of itraconazole. Drugs that reduce the gastric acidity impair the absorption of itraconazole from itraconazole capsules (see section 4.4). Effects of itraconazole on other medicines: Itraconazole is a potent inhibitor of CYP3A4 and inhibits the metabolism of medicines metabolised by this enzyme. This can result in an increase and/or a prolongation of their effects, including undesirable effects (see section 4.3). Thus, itraconazole should not be used in combination with other medicines metabolised by CYP3A4 unless the plasma levels, effects or undesirable effects of the co-administered drug are closely monitored. Itraconazole is a potent P-glycoprotein inhibitor, resulting in increased plasma level of P-gp substrates such as digoxin and dabigatran etexilate. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism. After stopping treatment, itraconazole plasma concentrations decline 6

7 gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered. Contraindications of concomitant use (see section 4.3): Terfenadine: Itraconazole inhibits the metabolism of terfenadine. Cases of cardiac effects, such as QT prolongation and rare occurences of torsades de pointes, have been reported in patients treated concomitantly with this drug. Astemizole: Itraconazole (400 mg/day for two weeks) has been observed to increase astemizole s AUC 0- threefold and to double the terminal half-life (from 2.1 to 3.6 days). This can lead to QT prolongation and rare occurrences of torsade de pointes. Pimozide, cisapride: Azole antimycotics inhibit the metabolism and increase the serum level of these drugs. This can lead to QT prolongation, cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Dofetilide, mizolastine: Itraconazole may induce markedly increased plasma concentrations of dofetilide and mizolastine resulting in a higher risk of adverse events such as QT prolongation and rare occurrences of torsade de pointes. Quinidine: Itraconazole (200 mg/day) has been observed to produce a 2.4-fold increase in quinidine's AUC. This can lead to QT prolongation and rare occurrences of torsade de pointes. Bepridil, nisoldipine, levacetylmethadol (levomethadyl) and sertindole: Co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare accurrences of torsade de pointes. Triazolam, oral midazolam: Itraconazole (200 mg/day) has been observed to produce a 27-fold increase in triazolam's AUC. The interaction with midazolam is a 10-fold increase in midazolam s AUC. HMG-CoA reductase inhibitors metabolised by CYP3A4 such as lovastatin, simvastatin and atorvastatin: Itraconazole inhibits the metabolism of simvastatin which may result in a more than 10-fold increase in the exposure to the active metabolite simvastatin acid. The metabolism of atorvastatin is inhibited resulting in a 3-fold increase of AUC. Ergot alkaloids (e.g. ergometrine (ergonovine), methylergometrine, ergotamine and dihydroergotamine): Itraconazole inhibits the CYP3A4-catalysed metabolism of ergot alkaloids. This may lead to severe vasoconstriction (ergotism) which can cause necrosis in arms and legs. Dabigatran etexilate Itraconazole is a potent P-gp inhibitor, and based on in vitro results increased plasma exposure to dabigatran is expected upon co-administration of itraconazole with dabigatran etexilate. The combination is contraindicated. Other drugs that are contraindicated with itraconazole: Eletriptan and ranolazin. Concomitant use not recommended (see section 4.4) 7

8 CYP3A4 metabolised calcium channel blockers such as dihydropyridines, verapamil, and felodipine: Caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. 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 itraconazole. An interaction study with 200 mg itraconazole administered once daily for four days followed by a dose of 5 mg felodipine reported a 6-fold increase in AUC and an 8-fold increase in C max for felodipine. CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, carbamazepine, isoniazid and St. John s Wort): Rifampicin: Rifampicin has been shown to induce the metabolism of itraconazole resulting in significantly lower (60-90%) plasma levels and, thus, a risk of no effect. Rifabutin: Itraconazole s C max and AUC were reduced by 70-75%. A case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis when given concomitantly with itraconazole. Such concomitant treatment should be avoided. Phenytoin: After daily administration of 300 mg phenytoin for 15 days, the AUC for a 200 mg dose of itraconazole decreased by more than 90%. Itraconazole's half-life went down from 22.3 hrs to 3.8 hrs. Concomitant use that require precautions including possible dose adjustment Caution should be exercised when co-administering itraconazole and other medicinal products metabolised by CYP3A4. For the below medicines, the plasma levels, effects or adverse events should be monitored and the dose possibly reduced. It should be noted that the information below regarding CYP3A4 substrate is not a complete list and that itraconazole can interact with other medicinal products metabolised by CYP3A4. P-gp substrates such as digoxin: Itraconazole is a potent P-gp inhibitor. Case reports show that administration of itraconazole to patients treated with digoxin can result in markedly increased plasma levels of digoxin with symptoms of digoxin intoxication. Itraconazole decreases the renal clearance of digoxin, probably through inhibition of P-gp, which is responsible for the active secretion of digoxin. If concomitant treatment with the two drugs is necessary, the digoxin plasma levels must be closely monitored. Drugs that reduce the gastric acidity such as acid neutralizing medicines, H 2 -antagonists and proton pump inhibitors (see section 4.4): Absorption of itraconazole is impaired when gastric acidity is reduced. Co-administration of omeprazole and itraconazole reduces the plasma concentration and AUC for itraconazole by approximately 65%, probably due to reduced absorption which is ph-dependent. Esomeprazole is assumed to show a similar interaction. Warfarin: Preliminary observations indicate that itraconazole may potentiate the effect of warfarin. Careful monitoring of the prothrombin time is necessary for this combination. HIV protease inhibitors such as ritonavir, indinavir and saquinavir: No experimental studies have been performed, but since protease inhibitors are mainly metabolised via CYP3A4, co-administration is likely to lead to elevated plasma concentrations. Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate: 8

9 Itraconazole can inhibit the metabolism of these agents. Busulphan s clearance was reduced by 20% in connection with concomitant use. Certain immunosuppressive agents such as cyclosporin, tacrolimusand sirolimus: Itraconazole may induce markedly increased plasma concentrations of these agents resulting in adverse events. The plasma concentration of cyclosporin, tacrolimus and sirolimus, respectively, should be monitored when used in combination with itraconazole. Certain glucocorticoids such as budesonide, dexamethasone, fluticasone and methylprednisolone: Dexamethasone: Itraconazole reduces clearance of intravenous dexamethasone by 68% by inhibiting CYP3A4. Methylprednisolone: Itraconazole reduces the metabolism of methylprednisolone. A 4-fold increase of its AUC and a doubling of the half-life have been observed. For long-term treatment in particular this involves a risk of steroid side effects if the methylprednisolone dose is not reduced. Alprazolam: Itraconazole has been observed to induce a 60% inhibition of alprazolam s clearance resulting in potentiated effects. Buspirone: Itraconazole increases buspirone s bioavailability (oral single dose) 19-fold. For combination treatment the buspirone dose must be drastically reduced. Other CYP3A4 substrates: alfentanil, brotizolam, cilostazol, disopyramide, ebastine, fentanyl, halofantrine, midazolam (intravenous), reboxetine, repaglinide: Itraconazole inhibits the metabolism of these agents. However, the clinical relevance is uncertain. No interaction of itraconazole with zidovudine (AZT) and fluvastatin has been observed. No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed. Effect on protein binding In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine. 4.6 Fertility, pregnancy and lactation Pregnancy /.../ capsules should not be given to pregnant women except in life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see section 4.3). When administered at high doses to pregnant rats (40 mg/kg/day or higher) and mice (80 mg/kg/day or higher), itraconazole has been shown to increase the incidence of foetal abnormalities and to produce adverse effects on the embryo (see section 5.3). 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. Breastfeeding 9

10 Very small amounts of itraconazole are excreted in human milk. The expected benefits of treatment with /.../ capsules should therefore be weighed against the potential risk of breast-feeding. In case of doubt the patient should not breast-feed. Fertility Women of childbearing potential using itraconazole should take adequate contraceptive precautions until their first menstrual period following the end of itraconazole therapy. 4.7 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 section 4.8), which may occur in some instances, must be taken into account. 4.8 Undesirable effects Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. In patients receiving prolonged (approximately 1 month) continuous therapy, the incidence of adverse events was higher (about 15%). The most frequently reported adverse experiences were of gastrointestinal, hepatic and dermatologic origin. Undesirable effects listed below have been reported in clinical trials with itraconazole capsules and/or from spontaneous reports from post-marketing experience for all itraconazole formulations. In clinical trials involving 2104 itraconazole-treated patients in the treatment of dermatomycoses or onychomycosis, the most frequently reported adverse experiences in clinical trials were of gastrointestinal, dermatological, and hepatic 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); (1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data). Adverse Drug Reactions Blood and lymphatic system disorders Leukopenia Not Known Neutropenia, thrombocytopenia Immune system disorders Uncommon Hypersensitivity* Not Known Anaphylactic reaction, anaphylactoid reaction, angioneurotic oedema, serum sickness Metabolism and nutrition disorders Not Known Hypokalemia, hypertriglyceridemia Nervous system disorders Uncommon Headache, dizziness, paraesthesia Hypoaesthesia Not Known Peripheral neuropathy* Eye disorders Not Known Visual disturbance Vision blurred and diplopia Ear and labyrinth disorder Tinnitus 10

11 Not Known Cardiac disorders Not Known Transient or permanent hearing loss* Congestive heart failure* Respiratory, thoracic and mediastinal disorders Not Known Pulmonary oedema Very Dyspnea Gastrointestinal disorders Common Abdominal pain, nausea Uncommon Vomiting, diarrhoea, constipation, dyspepsia, dysgeusia, flatulence Pancreatitis Hepatobiliary disorders Uncommon Hyperbilirubinaemia, alanine aminotransferase increased, aspartate aminotransferase increased Hepatic enzyme increased Not Known Acute hepatic failure*, hepatitis, hepatotoxicity* Skin and subcutaneous tissue disorders Common Rash Uncommon Urticaria, alopecia, pruritus Not Known Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity Musculoskeletal and connective tissue disorders Not Known Myalgia, arthralgia Renal and urinary disorders Pollakiuria Not Known Urinary incontinence Reproductive system and breast disorders Uncommon Menstrual disorder Not Known Erectile dysfunction General disorders and administration site conditions Uncommon Oedema Pyrexia * see section 4.4. Paediatric Population The safety of itraconazole oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of itraconazole oral solution for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were vomiting (36.0%), pyrexia (30.8%), diarrhoea (28.4%), mucosal inflammation (23.2%), rash (22.8%), abdominal pain (17.2%), nausea (15.6%), hypertension (14.0%), and cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 11

12 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Symptoms Nausea, abdominal pain, dizziness, headache and other of the described adverse reactions may occur and be intensified (see section 4.8). Treatment Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. Otherwise symptomatic treatment should be given. Itraconazole cannot be removed by haemodialysis. No specific antidote is available. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivative ATC-code: J02AC02 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. In vitro studies have shown that itraconazole inhibits the growth of a variety of human pathogenic fungi at concentrations usually ranging from to 0.8 µg/ml. Examples are: Candida albicans, many Candida non-albicans spp., Aspergillus spp., Trichosporon spp., Geotrichum spp., Cryptococcus neoformans, dermatophytes and many fungi belonging to the dematiaceae family such as Fonsecaea spp., Histoplasma spp., Pseudallescheria boydii and Penicillium marneffei. Candida glabrata and Candida tropicalis are usually the least sensitive Candida-species with some isolates showing clear resistance to itraconazole in vitro. The following types of fungi are not inhibited by itraconazole: Zygomycetes (i.e. Rhizopus spp., Rhizomucor spp., Mucor spp. och Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Paediatric Population The tolerability and safety of itraconazole 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 itraconazole 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 itraconazole were vomiting, abnormal liver function, and abdominal pain. 5.2 Pharmacokinetic properties Since itraconazole displays non-linear pharmacokinetics, a doubling of the dose will result in an almost 3-fold increase of the plasma concentration. The absolute bioavailability of an oral solution is 55%. The bioavailability of /.../ capsules is maximal when the capsules are taken immediately after a meal. However, the bioavailability is subject to large inter- and intraindividual variations. Peak plasma levels are reached 3 to 4 hours following an oral dose and steady state after 1 to 2 weeks of treatment. The plasma protein binding is 99.8%. Concentrations of itraconazole in whole blood are approx. 60% of those in plasma. Uptake in keratinous tissues, especially the skin, is up to 4 times higher than in plasma. The elimination of itraconazole from the skin is related to epidermal regeneration. Therapeutic levels persist for 2 to 4 weeks after discontinuation of a 4-week treatment. Detectable levels in nail keratin persist for at least 6 months after the end of a 3-month course of therapy. Fungicidal levels of 12

13 itraconazole in the vaginal epithelium persist for 3 days after end of treatment. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2 to 3 times higher than the corresponding plasma concentrations. After intravenous administration of itraconazole, total plasma clearance is approx. 380 ml/min and the distribution volume is approx. 11 l/kg. Plasma itraconazole is eliminated biphasically with a terminal half-life of 24 to 36 hours. Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole which has a comparable antifungal activity in vitro to itraconazole. Fungicidal levels measured by bio-assay were about 3 times those of itraconazole assayed by high-performance liquid chromatography (HPLC). 3 to 18% of the dose is excreted in faeces as unchanged substance. Excretion in urine is less than 0.03%. About 35% of a single dose is excreted as metabolites in urine within 1 week. Patients with impaired renal function or impaired immune system (e.g. in case of neutropenia or AIDS) may have a lower bioavailability of itraconazole (see section 4.4). Itraconazole inhibits human CYP3A4 (see section 4.5). Special Populations Paediatric Population Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which itraconazole oral solution was administered 5 mg/kg once or twice daily. The exposure to itraconazole was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective plasma concentrations of itraconazole were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment. 5.3 Preclinical safety data There are no preclinical safety data of relevance to the safety evaluation which are additional to that already included in other sections of this SPC. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sugar spheres (sucrose and maize starch), poloxamer and hypromellose. Capsule shell: Gelatin and colouring agents (indigo carmine (E 132), quinoline yellow (E 104) and titanium dioxide (E 171)). 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25 C. 6.5 Nature and contents of container Aluminium/Aluminium blisters: either 4, 6, 15, 18, 28, 30 or 100 capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal 13

14 No special requirements. 7. MARKETING AUTHORISATION HOLDER <[To be completed nationally]> 8. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION / DATE OF REVISION OF THE TEXT