ITRACONAZOLE100 MG CAPSULES HARD - summary of medicine characteristics

Itraconazole100 mg capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 100 mg of itraconazole.

Excipient: Each hard capsule contains 224.31 mg sucrose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule.

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

– Vulvovaginal candidiasis,

– Oral candidiasis,

– Dermatophytoses caused by organisms susceptible to itraconazole

(Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum,

– 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 itrakonazol 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 Amphotericine B,

-Maintenance therapy in AIDS patients to prevent relapse of underlying fungal infection who were found to be refractory or intolerant to first-line systemic anti-fungal therapy is inappropriate or has proved ineffective.

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.

4.2 Posology and method of administration

Route of administration: Oral use.

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

Capsules must be swallowed whole.

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 (200 mg 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 (200 mg o.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 pediatric use of this drug (see section 4.4).

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.

4.3 Contraindications

Itraconazole capsules are contraindicated in patients with known hypersensitivity to itraconazole or to any of the excipients.

Co-administration of the following drugs is contraindicated with itraconazole

capsules (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 capsules. Coadministration 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 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 capsules must not be used during pregnancy (except for lifethreatening cases). See Section 4.6.

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

4.4 Special warnings and precautions for use

Cross-hypersensitivity

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

Cardiac effects

In a healthy volunteer study with itraconazole IV, a transient asymptomatic decrease of the left ventricular ejection fraction was 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 itraconazole 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. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g., total daily dose), 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. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, itraconazole should be discontinued.

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 calcium channel blockers (see section 4.5) due to an increased risk of CHF.

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. Most of these cases 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. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving itraconazole 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. 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 such cases liver enzyme monitoring is necessary.

Reduced gastric acidity

Absorption of itraconazole from itraconazole capsules is impaired when gastric acidity is reduced. In patients also receiving acid neutralizing 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., H2-antagonists, proton pump inhibitors) it is advisable to administer itraconazole capsules with a cola beverage.

Use in children

Clinical data on the use of itraconazole capsules in paediatric patients is limited. Itraconazole capsules should not be used in paediatric patients unless the potential benefit outweighs 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.

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.

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 that may be attributable to itraconazole capsules, the treatment should be discontinued.

Disorders of Carbohydrate Metabolism

This drug 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 has a potential for clinically important drug interactions (see section 4.5).

Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John’s wort). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure.

4.5 Interaction with other medicinal products and other forms of interaction

Drugs affecting the absorption of itraconazole

Drugs that reduce the gastric acidity impair the absorption of itraconazole from itraconazole capsules (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, 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 itraconazole.

Effect 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 metabolism. After stopping treatment, itraconazole plasma concentrations 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.

Examples are:

The following drugs are contraindicated with itraconazole:

– Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with itraconazole 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 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.

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

Oral anticoagulants;

HIV protease inhibitors such as indinavir, ritonavir and saquinavir;

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

CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;

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

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

Digoxin (via inhibition of P-glycoprotein);

Others: alfentanil, alprazolam, brotizolam, buspirone, carbamazepine, cilostazol, disopyramide, ebastine, eletriptan, fentanyl, halofantrine, midazolam IV, reboxetine, repaglinide, rifabutin.

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, indometacin, tolbutamide and sulfamethazine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Itraconazole must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the fetus (see section 4.3).

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

There is limited information on the use of itraconazole during pregnancy. 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.

Women of childbearing potential

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

Lactation

A very small amount of itraconazole is excreted in human milk. The expected benefits of itraconazole capsules therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt, the patient should not breast-feed.

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

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); Rare (> 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

* see section 4.4.

4.9 Overdose

No data are available.

In the event of an overdose, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate.

Itraconazole cannot be removed by hemodialysis.

No specific antidote is available.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

ATC code: J02A C02

Mode of action

Itraconazole inhibits fungal 14a-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 ^0.125 mg/L and resistant >1 mg/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 < 1 mg itraconazole/L. There is no correlation between in vitro susceptibility and clinical efficacy.

Commonly susceptible species__________­_________________________

Aspergillus spp.___________­________________________­_____________________

Blastomyces dermatitidis1 2 3

Candida albicans___________­________________________­____________

Candida parapsilosis_________­________________________­_____________

Cladosporium spp. _____________­________________________­_________

Coccidioides immitis2

Cryptococcus neoformans___________­________________________­_____

Epidermophyton floccosum_________­________________________­____

Fonsecaea spp. 2

Geotrichum spp.___________­________________________­________________

Histoplasma spp.___________­________________________­_______________

Malassezia (formerly Pityrosporum) spp.___________­___________________

Microsporum spp.___________­________________________­____________

Paracoccidioides brasiliensis2

Penicillium marneffei2

Pseudallescheria boydii___________­________________________­___________

Sporothrix schenckii___________­________________________­______________

Trichophyton spp.___________­________________________­_________________

Trichosporon spp.___________­________________________­_________________

Species for which acquired resistance may be a problem___________

Candida glabrata__________­________________________­_____________

Candida krusei___________­________________________­_________________

Candida tropicalis4

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. Steadystate 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 hydroxyitraconazole 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 four-week 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 threemonth 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 AUG, were seen between these two groups. A statistically significant reduction in average Cmax (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.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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)

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

6.6    Special precautions for disposal