REGIONAL ADMINISTRATIVE INFORMATION

Transcription

1 MODULE 1: Module REGIONAL ADMINISTRATIVE INFORMATION Summary of Product Characteristics 1. Name of the medicinal product 2. Qualitative and quantitative composition Each capsule contains 100 mg of Itraconazole. Excipient: 195 mg Sucrose/capsule For a full list of excipients, see section Pharmaceutical form Capsule, hard Elongated, red opaque hard gelatine capsule (size 0) 4. Clinical particulars 4.1 Therapeutic indications - Vulvovaginal candidiasis, Oral candidiasis, Dermatomycoses (e.g. tinea corporis, tinea cruris, tinea pedis, tinea manus) and Onychomycoses (caused by dermatophytes and yeasts), Pityriasis versicolor. - Lymphocutaneous sporotrichosis, paracoccidioidomycosis, blastomycosis (in immunocompetent patients) and histoplasmosis. - Itraconazole can be used to treat patients suffering from invasive aspergillosis who were found to be refractory or intolerant to Amphotericin B. Consideration should be given to official guidance regarding the appropriate use of antifungal agents. NL H IB Itraconazol Heumann final SPC.doc 1

2 4.2 Posology and method of administration Itraconazole capsules are for oral use. The capsules should be taken immediately after meals. The capsules should be swallowed whole. Dosage recommendations for adults and adolescents: - Vulvovaginal candidiasis: 200 mg morning and 200 mg evening for 1 day. - Oral candidiasis: 100 mg once daily for 2 weeks. - Tinea corporis, tinea cruris: 100 mg once daily for 2 weeks. - Tinea pedis, tinea manus: 100 mg once daily for 4 weeks - Pityriasis versicolor: 200 mg once daily for 1 week. - Onychomycosis: Pulse therapy One pulse consists of two capsules twice a day for one week (400 mg/day), followed by a period of three weeks without medication. A total of three pulses are administered for onychomycosis in toenails, two pulses are recommended for onychomycosis in fingernails. Continuous treatment Two capsules (200 mg/day) once a day for 3 months. The treatment result will develop further after the end of medication as the nail grows. NL H IB Itraconazol Heumann final SPC.doc 2

3 - Lymphocutaneous sporotrichosis*: 100 mg once daily for 3 months. - Paracoccidioidomycosis*: 100 mg once daily for 6 months. - Blastomycosis*: 100 mg once daily, may be increased to 200 mg twice daily for 6 months. - Histoplasmosis*: 200 mg once daily, may be increased to 200 mg twice daily for 8 months. - Invasive aspergillosis: Start with a dosage of 200 mg three times daily for 4 days and then continue with 200 mg twice daily until the cultures are negative or until the lesions have disappeared (2-5 months duration) or at least until the neutropenia has ended. *) The treatment times specified are averages and can vary depending on the severity of the complaint or the clinical and mycological recovery. 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. - Children (below 12 years): There are inadequate data on itraconazole in children for its use to be recommended, unless the potential benefits outweigh the risks (see section 4.4). - Elderly: There are inadequate data on itraconazole in elderly for its use to be recommended, unless the potential benefits outweigh the risks. - Hepatic impairment: Itraconazole is predominantly metabolised in the liver. A slight decrease in oral bioavailability in cirrhotic patients has been observed, although this was not of statistical significance. The terminal half-life was only slightly, but statistically significantly, increased. The dose should be adapted if necessary. Monitoring of plasma levels may be necessary (see section 4.4). - Renal impairment: The oral bioavailability of itraconazole may be lower in patients with renal NL H IB Itraconazol Heumann final SPC.doc 3

4 insufficiency. Dose adaptation may be considered. Monitoring of plasma levels may be necessary. Itraconazole cannot be removed by dialysis (see section 4.4). - 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). 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. 4.3 Contraindications Itraconazole is contraindicated in: - Hypersensitivity to itraconazole or to related azole derivatives or to any of the other excipients. - Simultaneous administration of terfenadine, astemizole, cisapride, quinidine, pimozide, mizolastine, dofetilide, CYP3A4-metabolised HMG-CoA reductase inhibitors such as simvastatin, atorvastatin and lovastatin, oral midazolam, and triazolam. 4.4 Special warnings and precautions for use With itraconazole there is a possibility of clinically relevant interactions with other drugs (see section 4.5). - The absorption of itraconazole from is affected by a decrease in the ph of the stomach. Patients also treated with acid binders (e.g. aluminium hydroxide) must take these substances at least two hours after the administration of itraconazole. Patients suffering from achlorhydria, such as some AIDS patients or patients using acid inhibitors (e.g. H 2 -antagonists, proton pump inhibitors) are advised to take together with a carbonated soft drink having a low ph. - For patients undergoing continuous treatment lasting more than one month a liver function check is recommended. During administration of itraconazole severe liver toxicity occurred in very seldom cases, including several cases of acute fatal liver failure. In most cases it concerned patients who already had a liver disease previous to the treatment, who were treated for systemic indications, who suffered of other severe diseases and/or who were using other hepatotoxic agents. In some patients NL H IB Itraconazol Heumann final SPC.doc 4

5 there were no significant risk factors for liver diseases. Some of these cases occurred already in the first month of treatment: a few even in the first week. It should be considered to monitor the liver functions of patients that were treated with itraconazole frequently. Patients also need to be instructed to report signals and symptoms of hepatitis immediately to their physician, such as anorexia, nausea, vomiting, fatigue, abdominal pain, or dark urine. In these patients, treatment needs to be discontinued immediately and liver functions should be monitored. Itraconazole may not be prescribed to patients with pre-existing liver disorders or increased liver enzymes, nor to patients who showed liver toxicity as a reaction to other drugs. If the decision is made to start a long-term treatment, it is necessary to check the liver enzyme values during the treatment. - Long-term use (longer than 6 months or longer than 6 months cumulatively) is not recommended, except where there is no therapeutic alternative. - The oral bioavailability of itraconazole is lower in some patients with renal insufficiency. Adjusting the dose may be considered. - Hepatic insufficiency: Itraconazole is mainly metabolised in the liver. The terminal half-life time of itraconazole is somewhat longer in patients suffering from cirrhosis of the liver. The oral bioavailability of itraconazole is reduced in patients suffering from cirrhosis of the liver. Adjusting the dose may be considered. - The bioavailability of itraconazole may be reduced in some immunocompromised patients undergoing aggressive treatment with chemotherapeutics and antibiotics. For these patients it is therefore recommended to monitor the itraconazole concentration in the plasma and increase the dose if necessary. - In a study where itraconazole was administered intravenous in healthy subjects a temporary, asymptomatic reduction of the ejection fraction of the left ventricle has been observed that disappeared before the next infusion. The clinical relevance of this observation for oral formulations is unknown. - Itraconazole appears to have a negative inotropic effect and has been related to reports of decompensatio cordis. Itraconazole must not be used in patients with decompensatio cordis or with a history of decompensatio cordis unless the benefits are clearly higher than the risks. During this individual determination of the benefits and risks, factors such as the severity of the indication, the dosage and the individual risk factors for decompensatio cordis should be taken into consideration. These risk NL H IB Itraconazol Heumann final SPC.doc 5

6 factors include cardiac diseases such as ischemic and valvular diseases; important lung diseases such as chronic obstructive lung diseases; and kidney failure and other edema diseases. These patients need to be informed about the symptoms of congestive heart failure, they must be treated with care and monitored during their treatment on symptoms of decompensatio cordis; in case such symptoms occur during treatment, itraconazole administration should be discontinued. - Care should be taken when administering itraconazole and calcium channel blocking agents concomitantly (see section 4.5) - Itraconazole is a potent inhibitor of CYP 3A4. The use of itraconazole concomitantly with drugs metabolised by CYP 3A4 may lead to clinically relevant interactions (see section 4.5). Concomitant use of itraconazole and ergot alkaloids like ergotamine may result in higher levels of ergot alkaloids, due to CYP 3A4 inhibition of itraconazole. This may lead to symptoms of ergotism. - It is unknown whether cross-hypersensitivity can occur between itraconazole and other azole-antimycotics. Therefore caution should be taken when prescribing itraconazole to patients who are hypersensitive to other azole derivatives. - There is only little clinical experience of using itraconazole capsules in children. may therefore not be administered to children, except in cases where the expected positive effects outweigh the possible risks. - Because of the risk on damage to the foetus, women who are in their fertile age and use itraconazole should take adequate contraceptive measures until their first menstrual period following after the end of treatment. - Where neuropathy occurs which may be related to itraconazole the treatment must be discontinued. - Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, St. John s wort). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure. - Fluconazole-resistant strains of Candida species cannot be assumed to be susceptible to itraconazole. Ideally, susceptibility testing should be performed NL H IB Itraconazol Heumann final SPC.doc 6

7 before the start of itraconazole therapy. - This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Effects of other medicinal products on itraconazole: Itraconazole is mainly metabolised by CYP 3A4. Inducers of CYP3A4: Interaction studies have been performed with rifampicin, rifabutin and phenytoin which are potent inducers of CYP 3A4. The bioavailability of itraconazole and hydroxyitraconazole was decreased to such an extent that efficacy may be considerably reduced. The combination of itraconazole with potent enzyme inducers is not recommended. Similar effects should be anticipated for other enzyme inducers such as carbamazepine, phenobarbital and isoniazid. Also, itraconazole should not be given within two weeks of discontinuation of treatment with any medicinal product that induces CYP3A4. Inhibitors of CYP 3A4: As itraconazole is mainly metabolised through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of itraconazole. Examples are: ritonavir, indinavir, saquinavir, sildenafil, tadalafil, certain antineoplastic agents, sirolimus, clarithromycin and erythromycin. For concomitant use with sildenafil a dose reduction to 25 mg is recommended. Omeprazole: When itraconazole was administered with omeprazole (a proton pump inhibitor), the exposure of itraconazole was reduced by 65%. The interaction is probably due to reduced absorption, which is ph-dependent. Other proton pump inhibitors are expected to behave similarly (see section 4.2 and 4.4). Effects of itraconazole on the metabolism of other drugs: Itraconazole is a potent inhibitor of CYP 3A4 and inhibits the metabolism of drugs that are substrates of this enzyme. Itraconazole is also a potent P-glycoprotein inhibitor. NL H IB Itraconazol Heumann final SPC.doc 7

8 Concomitant administration of drugs that are substrates of CYP3A4 and/or P- glycoprotein with itraconazole may lead to an increase and/or a prolongation of their effects, and an increased risk of side effects Contraindicated combinations are: Terfenadine, astemizole, pimozide, cisapride, triazolam, orally administered midazolam, dofetilide, mizolastine and quinidine since co-administration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes, CYP 3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin, atorvastatin and lovastatin (see section 4.3). For interaction with ergot alkaloids see section 4.4. Concomitant use with the following drugs may require dose adjustment: Caution should be exercised when administering itraconazole with other CYP 3A4 substrates. Plasma levels, effects or side effects of the co-administered drug should be monitored and a dose adjustment may be necessary. It should be noted that the following list is not complete and itraconazole may interact with other drugs metabolised by CYP 3A4. Calcium channel blockers metabolized by CYP 3A4 (dihydropyridines, verapamil). Oral anticoagulants: Itraconazole may potentiate the effect of warfarin. It is recommended to monitor the prothrombin time if this combination is used. HIV protease inhibitors such as ritonavir, indinavir, saquinavir: Due to the fact that HIV protease inhibitors are mainly metabolised by CYP 3A4, increased plasma concentrations are expected if concomitantly used. Agents for treatment of erectile dysfunction such as sildenafil and tadalafil: Itraconazole may increase the plasma levels of these drugs with possible side effects as a consequence. Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate: NL H IB Itraconazol Heumann final SPC.doc 8

9 Itraconazole may inhibit the metabolism of these drugs. The clearance of busulfan was reduced by 20 % when concomitantly administered. Certain immunosuppressive agents: ciclosporin, tacrolimus, sirolimus: Itraconazole may increase the plasma levels of these drugs with possible side effects as a consequence. The plasma concentration of ciclosporin, tacrolimus and sirolimus must be monitored if used together with itraconazole. Digoxin: Itraconazole is known to inhibit P-gp. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin with symptoms of digoxin toxicity. Decreased digoxin urinary clearance has been suggested as itraconazole may inhibit the action of P-glycoprotein which transports digoxin out of kidney tubule cells into the urine. The digoxin plasma levels must be closely monitored during concomitant administration with itraconazole. Dexamethasone: Itraconazole reduces the clearance of intravenously administered dexamethasone by 68 %. Methylprednisolone: Itraconazole inhibits the metabolism of methylprednisolone. A 4-fold increase in exposure and a 2-fold increase in half life have been observed. There is a risk of steroid side effects, in particular during long term treatment, if the dose is not adjusted. Alprazolam: Concomitant administration of itraconazole and alprazolam led to a 60 % inhibition of alprazolam clearance. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Buspirone: Concomitant administration of itraconazole and buspirone (single oral dose) resulted in a significant increase (19-fold) in bioavailability. Dose adjustment is necessary when itraconazole and buspiron must be given concomitantly. Others:, alfentanil, brotizolam, carbamazepine, cilostazole, disopyramide, ebastine, NL H IB Itraconazol Heumann final SPC.doc 9

10 eletriptan, halofantrine, midazolam IV, reboxetine, repaglinide, rifabutin: The importance of the concentration increase and the clinical relevance of these changes during co-administration with itraconazole remains to be established. 4.6 Pregnancy and lactation Pregnancy Limited data with short-term use of itraconazole during pregnancy in women did not reveal harmful effects so far. There are no documented data on long-term use in pregnancy. In animal studies itraconazole has been shown to be harmful (see section 5.3). Itraconazole should not be used during pregnancy unless clearly necessary. Lactation Itraconazole is excreted in human breast milk. Breastfeeding is not recommended during treatment with itraconazole. 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 dizziness, which may occur in some instances, must be taken into account. 4.8 Undesirable effects In around 9% of the patients side effects can occur during administration of itraconazole. In long term use (around 1 month) the incidence of side effects was higher (around 15%). The most reported side effects that have been related to the use of itraconazole were of gastro-intestinal, hepatic and dermatological nature. Within every organic class the side effects are arranged to the frequency of occurrence: rare ( 0.01% to <0.1%); very rare (<0.01%), considering occasional reports. Based on postmarketing data the following side effects were reported as well: Blood and lymphatic system disorders: Very rare: thrombocytopenia. Immune system disorders: Very rare: anaphylactic, anaphylactoid and allergic reactions. Metabolism and nutrition disorders Very rare: hypokalaemia, hypertriglyceridaemia NL H IB Itraconazol Heumann final SPC.doc 10

11 Nervous system disorders Very rare: peripheral neuropathy, headache and dizziness Cardiac disorders Very rare: congestive heart failure Respiratory, thoracic and mediastinal disorders Very rare: lung oedema Gastrointestinal disorders Very rare: abdominal pain, vomiting, dyspepsia, nausea, diarrhoea and constipation Hepatobiliary disorders Very rare: acute fatal liver failure, severe hepatotoxicity, hepatitis, cholestatic jaundice and reversible increase of the liver enzymes Skin and subcutaneous tissue disorders Very rare: Stevens-Johnsons syndrome, angio-oedema, urticaria, alopecia, skin rash and pruritis Reproductive system and breast disorders Very rare: menstrual disorders General disorders and administration site disorders Very rare: oedema 4.9 Overdose No symptoms of overdosage are known. In case of overdosing the patient should be given something to drink and it should be attempted to induce vomiting, or a gastric irrigation should be carried out, after which activated charcoal and a laxative are given. There is no known antidote. Itraconazole is not removed by haemodialysis. NL H IB Itraconazol Heumann final SPC.doc 11

12 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivatives. ATC Code: J02A C02 General properties Itraconazole is a synthetic triazole compound having fungicidal action against dermatophytes, yeasts, Aspergillus spp. and other pathogenic fungi. Mechanism of action Itraconazole inhibits the biosynthesis of ergosterol, the most important sterol in the cellular membrane of yeasts and fungi at concentrations usually between and 0.8 µg/ml. This results in changes to the permeability and to the lipid components of the membrane. Microbiology The following organisms are taken to be sensitive to itraconazole: - Dermatophytes (Trichophyton spp., Epidermophyton floccosum, Microsporum spp.) - Yeast fungi (Candida albicans and other Candida spp., Pityrosporum ovale, Cryptococcus neoformans, Candida glabrata) - Aspergillus fumigatus and other Aspergillus spp. - Dimorphous fungi: Sporothrix schenckii, Histoplasma spp., Paracoccidioides brasiliensis, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis. Candida glabrata and Candida tropicalis are generally the least sensitive Candida species with some isolates definitely showing in vitro resistance to itraconazole. The most important fungal species not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Sensitivity in vitro is influenced by the size of the inoculum, the incubation temperature, the phase of growth of the fungus and in particular by the culture medium used. Considerable differences in the MIC values can therefore be found. NL H IB Itraconazol Heumann final SPC.doc 12

13 Other information Azole resistance appears to develop slowly and is often the result of several genetic mutations. Several mechanisms of resistance have been reported. One mechanism deals with a decreased affinity of 14α demethylase for the azole. This may result from overexpression or a point mutation in ERG11, the gene that encodes for 14α demethylase. Most commonly, resistance with azoles results form the fungal expression of an efflux pump system. It does not appear that fungi can transfer resistance genes from one unrelated organism to another and often clinical isolates are not related to each other. Fungal resistance will not likely result in large-scale decreases in fungal susceptibilities as experienced in bacterial resistance. Crossresistance between azole antifungals is reported among patients clinically resistant to clotrimazole. Manifold MIC increases towards itraconazole were observed so far only in laboratory selected mutants of Aspergillus fumigatus. 5.2 Pharmacokinetic properties The plasma levels vary greatly between individuals, both on single and on repeated administration. Absorption Maximum plasma levels of unchanged active substance are achieved within a period of 2-5 hours after intake. The absolute oral bioavailability of itraconazole is 55%. A maximum oral bioavailability is achieved if itraconazole is taken directly after a meal. Distribution The plasma-protein binding of itraconazole is 99.8%. In the blood 5% of itraconazole is bound to the blood cells, 95% is bound to plasma proteins, and only 0.2% is present in dissolved form. The concentration of itraconazole in whole blood is 60% of the plasma concentration. There are no data for humans on passage of itraconazole into breast milk. The tissue levels in keratin-containing tissue, especially skin and nails, are up to 4 times higher than the plasma levels. Itraconazole elimination from the skin depends on the regeneration of the epidermis; for nails the growth rate determines the elimination. Therefore, therapeutic levels continue to exist in the skin for 2 to 4 weeks after a treatment of a few weeks; for nails this period is 6-9 months. NL H IB Itraconazol Heumann final SPC.doc 13

14 Itraconazole is excreted onto the skin through the sebaceous glands and to a lesser extent through the sweat glands. It also reaches the epidermis via the keratinocytes of the basal stratum. Itraconazole also shows good penetration in other tissues which can be attacked by fungal infection. Concentrations of 2 to 3 times the corresponding plasma concentrations have been measured in lungs, kidneys, liver, bones, stomach, spleen and muscles. In vaginal tissue a therapeutic concentration continues to be present for 2 to 3 days after 2 administrations of 2 capsules on one day. After a 3-day treatment with 2 capsules once a day a therapeutic concentration continues to be present in vaginal tissue for 2 days. Biotransformation Itraconazole is metabolised in the liver, mainly by the CYP3A4 isoenzyme. One of the metabolites is hydroxy-itraconazole which in vitro shows antifungal action comparable to that of itraconazole. Levels determined using bioassays are therefore approximately three times as high as itraconazole levels determined with HPLC. Elimination The terminal half-life of itraconazole is 17 hours after single administration and increases to hours in repeated administration. The pharmacokinetics of itraconazole are characterized by non-linearity, consequently, the active substance accumulates in plasma after multiple administration. Steady state concentrations are achieved within 15 days with C max values reaching 0.5 µg/ml after 100 mg itraconazole once daily, 1.1 µg/ml after 200 mg itraconazole once daily, and 2.0 µg/ml after 200 mg twice daily. If treatment is terminated, the plasma concentrations of itraconazole fall almost below the detection limit within 7 days. Due to a saturation mechanism during metabolization in the liver, the itraconazole clearance decreases at higher dosage. 3-18% of the dose taken is excreted with the faeces as unchanged itraconazole. The content of unchanged itraconazole in the urine is less than 0.03%. In the liver itraconazole is metabolised to a large number of metabolites which are excreted with the faeces and the urine. Approximately 40% of this is excreted with the urine. 5.3 Preclinical safety data Subacute and chronic toxicity studies showed undesirable effects in adrenals, liver and NL H IB Itraconazol Heumann final SPC.doc 14

15 ovaries of female rats. Fat metabolism was impaired in rats. Nonclinical studies did not indicate a capacity for the development of genetic mutations. Toxic effects occurred at clinical relevant plasma levels. The clinical relevance for the observed effects in animal studies is unknown. In preclinical studies in male rats, there was a higher incidence of soft-tissue sarcoma at the end of a 2-year treatment. The potential risk for humans is unknown. There is no evidence of a primary influence on fertility under treatment with itraconazole. Itraconazole was found to cause dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice in high doses. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia. 6. Pharmaceutical particulars 6.1 List of excipients Capsule content: Sugar spheres (sucrose/maize starch) Hypromellose (E464) Sorbitan stearate (E491) Colloidal hydrated silica (E551) Capsule Cap/body: Gelatin Red iron oxide (E172) Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 3 years. 6.4 Special precautions for storage Do not store above 2530 C. NL H IB Itraconazol Heumann final SPC.doc 15

16 6.5 Nature and contents of container PVC/PVdC/Aluminum blister NL/H/640/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/641/01 Blister containing 4, 6, 7, 8, 14, 15, 16, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 and 500 capsules in strips. NL/H/642/01 Blister containing 4, 6, 7, 8, 10, 14, 15, 18, 20, 28, 30, 50, 56, 60, 84, 100, 140, 150, 200, 250, 280, 300, 500 and 1000 capsules in strips. NL/H/643/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/644/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/645/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/646/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/647/01 Blister containing 4, 6, 8, 14, 15, 18, 28, 30, 60, 84, 100x1 capsules in strips. NL H IB Itraconazol Heumann final SPC.doc 16

17 NL/H/648/01 Blister containing 14, 28, 30 capsules in strips. NL/H/649/01 Blister containing 14, 28, 30 capsules in strips. NL/H/650/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. NL/H/651/01 Blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, 300 capsules in strips. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER 8. MARKETING AUTHORISATION NUMBER 9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION 10. DATES OF REVISION OF THE TEXT NL H IB Itraconazol Heumann final SPC.doc 17