Itraconazole 100mg Capsules

Itraconazole 100 mg.

For excipients, see 6.1

Capsule, hard

(Size 0), opaque green, containing coated beads.

Indications

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

Itraconazole is indicated for the treatment of the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective (eg. because of underlying pathology, insensitivity of the pathogen or drug toxicity):

Itraconazole Capsules is for oral administration and must be taken immediately after a meal for maximal absorption. Treatment schedules in adults for each indication are as follows:

For skin infections, optimal clinical and mycological 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.

In Acquired Immune Deficiency Syndrome and neutropenic patients: for the treatment of oral candidiasis 200 mg 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:

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

Itraconazole is contraindicated in:

• Hypersensitivity to itraconazole or to any of the capsule excipients.

• Pregnancy. However, itraconazole may be given if the fungal infection is life-threatening and the potential benefit is considered to outweigh the potential risk to the foetus. Adequate contraceptive precautions should be taken by women of childbearing potential using Itraconazole until the next menstrual period following the end of therapy.

• Patients taking terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin, triazolam and oral midazolam Capsules (see also 4.5 Interactions with Other Medicaments and Other Forms of Interactions).

• 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.

• In a healthy volunteer study with intravenous Itraconazole, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

• Itraconazole has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. 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 dose and duration of treatment, and individual risk factors for congestive heart failure. 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.

• Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5, Interactions with other medicinal products).

• Itraconazole has a potential for clinically important drug interactions. (See 4.5: Interaction with other medicaments and other forms of interaction).

•Decreased gastric acidity:

Absorption of itraconazole is impaired when gastric acidity is decreased. In patients also receiving acid neutralising medicines (e.g. aluminium hydroxide) these should be administered at least 2 hours after the intake of Itraconazole Capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (e.g. H₂-antagonists. proton-pump inhibitors) it is advisable to administer Itraconazole Capsules with a cola beverage.

• Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. Some of these cases involved patients with no pre-existing 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. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or 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.

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

•Renal Impairment:

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.

• If neuropathy occurs which may be attributable to Itraconazole, treatment should be discontinued.

• Fluconazole-resistant strains of Candida species cannot be assumed to be susceptible to itraconazole. Ideally, susceptibility testing should be performed before the start of Itraconazole therapy.

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

(1) Drugs affecting the metabolism of itraconazole:

Interaction studies have been performed with rifampicin, rifabutin and phenytoin. Since the bioavailability of itraconazole and hydroxyitraconazole was decreased in these studies to such an extent that efficacy may be considerably 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.

As itraconazole is mainly metabolised through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of itraconazole. Examples are: ritonavir, indinavir and clarithromycin and erythromycin.

(2) Effects of itraconazole on the metabolism of other drugs:

Itraconazole can inhibit the metabolism of drugs that are substrates for cytochrome 3A isoenzymes. This can result in an increase and/or a prolongation of their effects, including side effects. 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 co-administered drugs is considered.

Examples are:

• Drugs which must not be used during treatment with itraconazole:

Terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin (see section 4.3).

• Caution should be exercised when co-administering itraconazole with calcium channel blockers. 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.

If the following are co-administered with itraconazole, their plasma levels, clinical effects and possible side effects should be monitored. The dose of these drugs may need to be reduced during co-administration with itraconazole:

• 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: cyclosporin, tacrolimus, sirolimus

• Others: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, ebastine, reboxetine. The importance of the concentration increase and the clinical relevance of these changes during co-administration with itraconazole remain to be established.

Pregnancy: 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.

Studies of the use of itraconazole in pregnant women are not available. Therefore Itraconazole should only be given in life-threatening cases of systemic mycosis and when the potential benefit outweighs the potential risk to the foetus.

Lactation: A very small amount of itraconazole is excreted in human milk. The expected benefits of Itraconazole therapy should be weighed against the risks of breast-feeding. In case of doubt, the patient should not breast-feed.

None known.

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 was higher (about 15%). The most frequently reported adverse experiences were of gastrointestinal, hepatic and dermatological origin.

Based upon the post-marketing experience, the following adverse reactions have been reported very rarely (<1/10,000):

•Metabolism and Nutrition Disorders

hypokalaemia

•Nervous System Disorders

peripheral neuropathy, headache, and dizziness

•Cardiac Disorders

congestive heart failure

•Respiratory, Thoracic and Mediastinal Disorders

pulmonary oedema

•Gastrointestinal Disorders

abdominal pain, vomiting, dyspepsia, nausea, diarrhoea and constipation

•Hepato-Biliary Disorders

fatal acute liver failure, serious hepatotoxicity, hepatitis, reversible increases in hepatic enzymes

•Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, angio-oedema, urticaria, alopecia and rash, and pruritus

•Reproductive System and Breast Disorders

menstrual disorder

•General Disorders and Administrative Site Conditions

allergic reaction, and oedema

In the event of an accidental overdose, 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.

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

Peak plasma concentrations of itraconazole in the region of 1 mcg 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%.

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

Sugar spheres

Poloxamer 188

Hypromellose

Capsule shell.

Titanium dioxide (E171)

Indigo carmine (E132)

Gelatin

Quinoline yellow (E104)

None known.

2 years.

Do not store above 25°C.

Store in the original package.

Aluminium-Aluminium blister

Pack sizes: 4, 6, 14, 15, 18, 28, 60, 84, 100 capsules.

Not applicable

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

PL 04416/0555

6^th July 2004