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Itraconazole 100mg Capsules

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Itraconazole 100 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains Itraconazole 100 mg.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Itraconazole is indicated for the treatment of the following fungal infections:

1. Vulvovaginal candidiasis.

2. Pityriasis versicolor.

3. Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp. Microsporum spp. Epidermophyton floccosum) e.g. tinea pedis; tinea cruris; tinea corporis; tinea (manuum).

4. Oropharyngeal candidiasis.

5. Onychomycosis caused by dermatophytes and/or yeasts.

6 Histoplasmosis.

7. Itraconazole is indicated in the treatment of the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity.

-Aspergillosis

-Candidiasis

-Cryptococcosis and cryptococcal meningitis

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

4.2 Posology and method of administration

Itraconazole is for oral administration and must be taken immediately after a meal for maximal absorption.

Indication	Dose
Vulvovaginal candidosis	2 capsules (200mg) twice daily for 1 day
Pityriasis versicolor	2 capsules (200mg) once daily for 7 days
Tinea corporis, tinea cruris	1 capsule (100mg) once daily for 15 days
Tinea pedis, tinea manuum	1 capsule (100mg) once daily for 30 days
Oropharyngeal candidosis	1 capsule (100mg) once daily for 15 days
Onychomycosis	2 capsules (200mg) once daily for 3 months.

For skin infections, optimal clinical and mycological effects are reached 1 - 4 weeks after cessation of treatment and for nail infections, 6 - 9 months after the cessation of treatment. This is because elimination of itraconazole from skin and nails is slower than from plasma.

In Acquired Immune Deficiency Syndrome and neutropenic patients: for the treatment of oral candidosis a higher dosage of 2 capsules (200mg) once daily for 15 days is recommended due to the impaired absorption of itraconazole in these patient groups.

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

Indication	Dose	Remarks
Aspergillosis	200mg once daily	Increase dose to 200mg twice daily in case of invasive or disseminated disease
Candidosis	100-200mg once daily	Increase dose to 200mg twice daily in case of invasive or disseminated disease
Non-meningeal cryptococcosis	200mg once daily
Cryptococcal meningitis	200mg twice daily
Histoplasmosis	200mg once daily - 200mg twice daily
Maintenance in AIDS	200mg once daily	See note on impaired absorption below
Prophylaxis in neutropenia	200mg once daily	See note on impaired absorption below

Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases blood level monitoring and if necessary an increase in itraconazole dose to 200mg twice daily is indicated.

In 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.

In Elderly : As for use in children.

4.3 Contraindications

Itraconazole is contraindicated in:

1. Itraconazole capsules must not be used during pregnancy (except for life-threatening cases). See section 4.6 Pregnancy & Lactation.

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.

2. Patients who have shown hypersensitivity to itraconazole or its excipients.

3. Patients taking any of the following medicinal products: (see also section 4.5 Interactions with other medicinal products and other forms of interaction)

• CYP3A4 metabolized 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. 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, simvastatin and lovastatin

• Triazolam and oral midazolam

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

• Eletriptan

• Nisoldipine

4. 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.

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 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 regime (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 signifant other medical conditions and/or were taking hepatotoxic drugs. Some patients had no obvious risk factors for 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 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 is impaired when gastric acidity is reduced. 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. 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).

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 however significantly increased. The dose should be adapted if necessary.

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 nonmeningeal) 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

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

In systemic candidiasis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole. Ideally, 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 CYP 3A4 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

1. Drugs affecting the absorption of itraconazole

Drugs that reduce the gastric acidity impair the absorption of itraconazole from SPORANOX capsules (see section 4.4).

2. 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 enzyme inhibitors of CYP3A4. Since the bioavailability of itraconazole and hydroxyl-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.

3. Effects of itraconazole on the metabolism of other drugs

3.1 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 levels decline gradually, depending on the dose and duration of treatment (see Section 5.2 Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of itraconazole on comedicated 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, simvastatin and lovastatin.

• 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 co-administered with itraconazole, should be reduced if necessary:

• Oral anticoagulants

• HIV protease inhibitors such as ritonavir, indinavir, saquinavir

• Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel and

trimetrexate

• CYP3A4 metabolised calcium channel blockers such as dihydropyridines and

verapamil

• Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also

known as sirolimus)

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

• Digoxin (via inhibition of P-glycoprotein)

• Others: carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, cilostazol,

disopyramide, eletriptan, fentanyl, halofantrine, midazolam IV, rifabutin, ebastine, reboxetine, repaglinide.

3.2 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.

4. 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 or sulfamethazine.

4.6 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. When administered at high doses to pregnant rats (40mg/kg/day or higher) and mice (80mg/kg/day or higher), itraconazole was shown to increase the incidence of foetal abnormalities and produced adverse effects on the embryo.

There is limited information on the use of itraconazole during pregnancy. During postmarketing 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 therapy should therefore be weighed against the potential risk of breastfeeding. 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).

Adverse Drug Reactions

Blood and lymphatic system disorders
Rare	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
Rare	Hypoaesthesia
Not Known	Peripheral Neuropathy*

Eye disorders
Rare	Visual Disturbance
Not Known	Vision Blurred and Diplopia

Ear and labyrinth disorder
Rare	Tinnitus
Not Known	Transient or permanent Hearing Loss*

Cardiac disorders
Not Known	Congestive Heart Failure*

Respiratory, thoracic and mediastinal disorders
Not Known	Pulmonary Oedema

Gastrointestinal disorders
Common	Abdominal Pain, Nausea
Uncommon	Vomiting, Diarrhoea, Constipation, Dyspepsia, Dysgeusia; Flatulence
Rare	Pancreatitis

Hepatobiliary disorders
Uncommon	Hyperbilirubinaemia, Alanine Aminotransferase Increased, Aspartate Aminotransferase Increased
Rare	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, Angiooedema, Erythema Multiforme, Exfoliative Dermatitis, Leukocytoclastic Vasculitis, Photosensitivity

Musculoskeletal and connective tissue disorders
Not Known	Myalgia, Arthralgia

Renal and urinary disorders
Rare	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
Rare	Pyrexia
Not Known	Allergic reaction

see section 4.4.

4.9 Overdose

No data are available.

In the event of accidental overdosage, patients should be treated symptomatically with supportive measures. Within the first hour after ingestion gastric lavage may be performed. Activated charcoal may be given if appropriate.

No specific antidote is available. Itraconazole cannot be removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Itraconazole is a substituted triazole antimycotic with a broad spectrum of activity against Candida spp and other yeasts, dermatophytes and some other pathogenic fungi. It acts by impairing the synthesis of ergosterol in fungal cell membranes.

5.2 Pharmacokinetic properties

Peak plasma concentrations of itraconazole in the region of 1mcg equiv/ml are reached 1.5-3 hrs after administration. In man, the elimination half-life is about 20 hrs. Oral intake immediately after a meal doubled the peak level 3-4 hrs after intake.

Peak concentrations of itraconazole in keratinous tissues, especially skin, are up to 3 times higher than in plasma. Therapeutic levels in the skin persist for up to 2-4 weeks after stopping treatment as elimination is related to epidermal regeneration, rather than redistribution into the systemic circulation.

Itraconazole is extensively metabolised by the liver to a large number of metabolites, which constitute 40% of the excreted dose. Faecal excretion of parent drug varies from 3-18% of the dose, and urinary excretion of unchanged drug is less than 0.03%.

5.3 Preclinical safety data

There is no other relevant information in addition to that provided in previous sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sugar spheres Hypromellose (E464)

Sorbitan stearate Silica colloidal hydrated

Capsule shell:

Titanium dioxide (E171) Red iron oxide (E172) Gelatin

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5 Nature and contents of container

Aluminium/PVC/PVDC blister containing 4, 6, 7, 8, 14, 15, 18, 28, 30, 50, 60, 84, 100, 140, 150, 280, and 300 capsules in strips

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd Station Close Potters Bar Hertfordshire EN6 1TL

MARKETING AUTHORISATION NUMBER

PL 04569/0810

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/11/2010

10 DATE OF REVISION OF THE TEXT

08/06/2011