Itraconazole 100mg Capsules, hard

Each capsule, hard contains 100mg of itraconazole.

Excipient: Each capsule, hard contains 224.31mg sucrose.

For a full list of excipients, see section 6.1.

Capsule, hard.

No. 0 hard gelatin capsules, opaque green cap and body, containing yellowish-beige spherical micro-granules

- Vulvovaginal candidiasis,

- Oral candidiasis

- Dermatomycoses,

- Pityriasis versicolor,

- Onychomycoses caused by dermatophytes and/or yeasts,

- Systemic candidiasis,

- Cryptococcal infections (including cryptococcal meningitis). In immunosuppressed patients suffering from cryptococcosis and in patients with cryptococcosis of the CNS Itraconazole is indicated only if the usually recommended initial therapy seems to be inappropriate or ineffective

- Histoplasmosis.

- Aspergillosis. Itraconazole can be used to treat patients suffering from invasive aspergillosis who were found to be refractory or intolerant to Amphotericin B

Due to PK properties, orally administered itraconazole (capsules) should not be used as the initial treatment in patients with severe life-threatening forms of systemic mycoses. Oral forms should be used as a continuation therapy, after initial treatment with i.v. itraconazole (see section 4.4).

Consideration should be given to official guidance regarding the appropriate use of antifungal agents.

Route of administration: Oral use.

For maximum drug absorption itraconazole should be taken immediately following a meal.

Capsules must be swallowed whole.

¹ for infections in areas that are highly keratinized, such as plantar Tinea pedis (fungal foot infection) and palmar Tinea manus (fungal infections of the palm), patients must take 200mg b.i.d. for 7 days, or 100mg once a day for 30 days.

² in some patients with compromised immune systems, such as neutropenic, AIDS or transplant patients, the bioavailability of oral itraconazole may be diminished. In these cases the dose may have to be doubled.

Onychomycoses

Onychomycoses can be treated using a pulse or a continuous regime.

- Pulse treatment (see table below):

Pulse itraconazole treatment consists of taking two capsules twice a day (200mg b.i.d.) for one week.

For fingernail infections two pulse treatments are recommended, and for toenail infections, three. Each pulse should be separated by a period of three weeks with no treatment. Clinical response can be seen by in the form of nail growth when the treatment is ended.

- Continuous treatment:

Two capsules a day (200mg q.d.) for three months.

The rate of elimination of itraconazole in skin and nail tissue is slower than in blood plasma. Optimum clinical and mycological response is reached two to four weeks after treatment for skin infections, and six to nine months after treatment for nail infections.

Systemic mycoses (doses vary depending on the infecting organism)

The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy:

- 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.

Use in children

Itraconazole should not be administered to children as there is limited clinical data describing the paediatric use of this drug (see section 4.3).

Use in elderly patients

Not recommended

Use in patients with hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (see section 5.2)

Use in patients with 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.

Itraconazole 100mg Capsules, hard is contraindicated in patients with a known hypersensitivity to itraconazole or any of the excipients.

Itraconazole must not be used during pregnancy and lactation, with the exception of life-threatening conditions (see section 4.6).

Children: there is limited experience with itraconazole in pediatric patients; therefore itraconazole should not be administered to children unless the expected benefits outweigh the risks (see section 4.2).

Coadministration of the following drugs is contraindicated with Itraconazole 100mg Capsules, hard (see also section 4.5):

- 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 Itraconazole 100mg Capsules, hard. 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 atorvastatin, lovastatin and simvastatin.

- Triazolam and oral midazolam.

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Eletriptan.

- Nisoldipine.

- Itraconazole 100mg Capsules, hard 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)

In a test using healthy volunteers given i.v. itraconazole, a transitory asymptomatic decrease in the left ventricle ejection fraction was observed. This was resolved before the following infusion. The clinical relevance of these results to oral use of itraconazole is not known.

Itraconazole has been shown to have a negative inotropic effect, and itraconazole 100 mg has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400mg 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.”

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole (see section 4.5).

Itraconazole has the potential for important interactions with other drugs. (see section 4.5)

Women of childbearing potential have to use effective contraception during and up to 4 weeks after treatment with itraconazole (see section 4.6).

Decreased stomach acid: decreased stomach acid will hamper the absorption of itraconazole. In patients who are being treated with stomach acid neutralizers (e.g. aluminium hydroxide), these drugs must be administered two or more hours before itraconazole. In patients with achlorhydria, such as some AIDS patients and patients receiving acid secretion suppressors such as H₂-antagonists or proton pump inhibitors, itraconazole should be taken with a cola drink.

There are very rare reports of severe hepatotoxicity, including some cases of fatal acute liver failure following itraconazole treatment. Most of these cases were reported in patients with pre-existing liver disease or treated for systemic infections and patients with other medical conditions and/or taking other hepatotoxic drugs. Some patients had no notorious liver disease factors. Several cases were observed in the first month of treatment, including some cases in the first week. Monitoring hepatic function should be a consideration when treating patients with itraconazole. Patients must be instructed to report signs and symptoms of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. If patients present any of these symptoms treatment must be immediately suspended and tests conducted to measure hepatic function. Treatment should not be initiated in patients who present increased liver enzymes, active liver disease, or who present liver toxicity to other drugs, unless the expected benefits of treatment with itraconazole outweigh the risks of hepatic lesions. In this case liver enzymes must be closely monitored.

Hepatic impairment: Itraconazole metabolizes fundamentally in the liver. Bioavailability of oral itraconazole in patients with cirrhosis will be somewhat diminished. The terminal half-life is significantly increased. Plasma levels of itraconazole should be monitored and the dose adjusted as necessary.

Treatment must be immediately discontinued if patients present neuropathy attributable to itraconazole.

Kidney failure: Bioavailability of oral itraconazole in patients with kidney failure will be somewhat diminished. Plasma levels of itraconazole should be monitored and the dose adjusted as necessary.

There is no information on crossed hypersensitivity to itraconazole and other azole antifungals. Care should be taken when prescribing itraconazole capsules to patients with sensitivity to other azoles.

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Itraconazole 100mg Capsules, hard may be decreased.

Care should be taken when administering itraconazole and calcium channel blocking agents concomitantly (see section 4.5).

Patients with life-threatening forms of systemic mycoses: Due to PK properties of itraconazole (see section 5.2) orally administered capsules are not recommended as the initial treatment of life-threatening systemic mycoses.

Patients with AIDS: in patients with AIDS treated for systemic mycoses, such as sporotrichosis, blastomycosis or cryptococcosis, and where the risk of relapse is present, the need of holding course therapy should be considered.

This drug contains sucrose. Patients with rare hereditary fructose intolerance pathologies, sucroseisomaltose malabsorption or glucose-galactose malabsorption should not take this drug.

Drugs affecting the absorption of itraconazole

Drugs that reduce the gastric acidity impair the absorption of itraconazole from Itraconazole 100mg Capsules, hard (See section 4.4).

Drugs affecting the metabolism of itraconazole

Itraconazole is mainly metabolised through the cytochrome CYP3A4.

Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, 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 itraconazole.

Effects of itraconazole on the metabolism of other drugs

Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of administration. After stopping treatment, itraconazole plasma levels decline 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.

The following drugs are contraindicated with itraconazole:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Itraconazole 100mg Capsules, hard 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 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin.

- Triazolam and oral midazolam.

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Eletriptan

- Nisoldipine

Caution should be exercised when co-administering itraconazole 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 itraconazole.

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

- Oral anticoagulants;

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

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

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

- Certain immunosuppressive agents: cyclosporine, 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, loperamide. The importance of the concentration increase and the clinical relevance of these changes during co-administration with itraconazole remain to be established.

No interaction of itraconazole with zidovudine (AZT) and fluvastatine 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, indometacin, tolbutamide and sulfamethazine.

Pregnancy

Itraconazole 100mg Capsules, hard must not be used during pregnancy with the exception of life-threatening cases where potential benefits outweigh the risks (see section 4.3).

In animal studies itraconazole has shown reproduction toxicity (see section 5.3).

Epidemiological data on exposure to itraconazole during the first trimester of pregnancy – mostly in patients receiving short-term treatment for vulvovaginal candidosis – did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.

Women of childbearing potential

Women of childbearing potential taking Itraconazole 100mg Capsules, hard should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itraconazole 100mg Capsules, hard therapy.

Lactation

A very small amount of itraconazole is excreted in human milk. Itraconazole 100mg Capsules, hard must not be used during lactation.

No studies on the effects on the ability to drive and use machines have been performed.

Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. 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).

There is no data available. Support measures should be taken in the case of accidental intoxication, including gastric lavage within the first hour following ingestion. If deemed appropriate, activated charcoal can be given to the patient. Itraconazole will not be eliminated by hemodialysis and there is no specific antidote.

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

ATC code: J02A C02

Mode of action

Itraconazole 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 itraconazole, 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 itraconazole

• Drug-transporter over-expression resulting in increased efflux of itraconazole from fungal cells (i.e., removal of itraconazole 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 itraconazole have not yet been established for fungi using EUCAST methods.

Using CLSI methods, breakpoints for itraconazole have only been established for Candida species from superficial mycotic infections. The CLSI breakpoints are: susceptible 0.125mg/L and resistant >1mg/L.

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 itraconazole 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 itraconazole may vary widely. Susceptibility in the table below is based on MIC₉₀ < 1mg itraconazole/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 Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

³ Natural intermediate susceptibility.

General pharmacokinetic characteristics

The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing. In general, Itraconazole is rapidly absorbed. Peak plasma concentrations are reached within 2 to 5 hours after oral administration. Itraconazole is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-itraconazole, with plasma concentrations about twice those of unchanged itraconazole. The mean elimination half-life of itraconazole is about 17 hours after a single dose and increases to 34-42 hours after repeated dosing. Itraconazole has non-linear pharmacokinetics, and consequently itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. Plasma levels are undetectable 7 days after suspending itraconazole treatment. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with feces.

Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal.

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. Brain to plasma ratios were about 1 as measured in beagle dogs. The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma.

Biotransformation

Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.

As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Elimination

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with feces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas fecal excretion of unchanged drug varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Itraconazole absorption by keratinous tissue, especially skin, is four times that of plasma and itraconazole elimination is related to skin regeneration. Whereas plasma levels are undetectable 7 days after suspending itraconazole treatment, in skin therapeutic levels of the drug can be found for 2-4 weeks following the fourweek course of treatment. Levels of itraconazole were found in the nail keratin one week after start of treatment, persisting for a period of at least six months following a three-month treatment.

Special Populations

Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in average C_max (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole. (See sections 4.2 Posology and method of administration and 4.4 Special warnings and special precautions for use).

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

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.

Capsule content:

Sugar spheres (maize starch and sucrose)

Poloxamer 188

Hypromellose 6 cP

Capsule Cap/body:

Gelatin

Indigo carmine (E 132)

Quinoline Yellow (E 104)

Titanium dioxide (E 171)

Not applicable.

2 years

Do not store above 25°C.

Aluminum/aluminum blister pack

Packs of 4, 14, 15, 16, 28, 30, 32 and 60 capsules.

100 capsule packages for hospital use.

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC ehf.

Reykjavíkurvegur 76-78, 220 Hafnarfjörður

Iceland

PL 30306/0228

01.07.09

(IF APPLICABLE)

(IF APPLICABLE)