INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
SPORANOX™ capsules

SCHEDULING STATUS
Schedule 4.

PROPRIETARY NAME
(and dosage form)

SPORANOX™ capsules

COMPOSITION
Each capsule contains 100 mg of itraconazole in a pellet formulation.

PHARMACOLOGICAL CLASSIFICATION
A.20.2.2 Antimicrobial (chemotherapeutic) agents. Fungicides.

PHARMACOLOGICAL ACTION
Itraconazole is a synthetic broad-spectrum triazole antifungal agent, active in vitro against strains of the following: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Candida spp.), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Blastomyces dermatitidis. In vitro activity does not necessarily imply clinical efficacy.
In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol which is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect. Correlation between in vitro minimum inhibitory concentration (MIC) results and clinical outcome, has yet to be established for itraconazole.
The oral bioavailability of itraconazole is maximal when the capsules are given immediately after a full meal. Peak plasma levels are reached 3 to 4 hours following an oral dose. During chronic administration, steady-state is reached after 1-2 weeks. Steady-state plasma concentrations of itraconazole 3-4 hours after drug intake are 0,4 micrograms/mL (100 mg daily), 1,1 micrograms/mL (200 mg daily) and 2,0 micrograms/mL (200 mg twice daily). Elimination from plasma is biphasic with an elimination half-life of 1 to 1,5 days.
The plasma protein binding of itraconazole is 99,8%.
Concentrations of itraconazole in whole blood are 60% of those in plasma.
Uptake in keratinous tissues especially the skin, is up to 5 times higher than in plasma and elimination of itraconazole is related to epidermal regeneration. In contrast to the plasma levels which become undetectable within 7 days of stopping therapy, therapeutic levels in the skin persist for 2 to 4 weeks after discontinuation of a 4-week treatment. Levels of itraconazole in the nail keratin persist for at least 6 months after the end of a 3 month course of therapy.
Itraconazole is also present in sebum and to a lesser extent in sweat. Cerebrospinal fluid contains negligible amounts of the drug (0,002 times the serum level).
Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than the corresponding plasma concentration.
Therapeutic levels in vaginal tissue are maintained for another 2 days after discontinuation of a 3-day course with 200 mg daily and for another 3 days after discontinuation of a 1-day course with 200 mg twice daily.
Itraconazole is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole, which has a comparable antifungal activity in vitro to itraconazole. Antifungal drug levels measured by bio-assay were about 3 times those of itraconazole assayed by high performance liquid chromatography. Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0,03 % of the dose. About 35% of the dose is excreted as metabolites in the urine within one week.

INDICATIONS
SPORANOX capsules are indicated for:

1)	Persistent vulvovaginal candidiasis which does not respond to conventional therapy.
2)	Dermatomycosis which does not respond to conventional therapy.
3)	Although proof of efficacy is limited, SPORANOX capsules have been used in fungal keratitis.
4)	Onychomycosis, caused by dermatophytes and/or yeasts and which does not respond to other therapy.
5)	Although proof of efficacy is limited, SPORANOX capsules have been used in: systemic aspergillosis and candidiasis, histoplasmosis, sporotrichosis, paracoccidioidomycosis and blastomycosis.

CONTRA-INDICATIONS

SPORANOX capsules are contra-indicated in pregnant women. Adequate contraceptive precautions should be taken by women of childbearing potential during therapy and for one menstrual cycle after stopping therapy, as teratogenicity has been shown in laboratory animals.

Terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin, oral midazolam and triazolam should not be used during treatment with SPORANOX capsules.
SPORANOX capsules are also contra-indicated in patients with a known hypersensitivity to itraconazole or its excipients, other azole antifungal agents or any of the excipients.
SPORANOX has been shown to have no benefit in the prophylaxis of cryptococcal meningitis in HIV-infected patients.
SPORANOX should not be administered to treat onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Rare cases of CHF and pulmonary oedema have been reported in the post-marketing period in patients treated with SPORANOX capsules. These patients were being treated for onychomycosis and/or systemic fungal infection. If signs or symptoms of CHF occur during administration of SPORANOX capsules, discontinue administration.

WARNINGS
Itraconazole is predominantly metabolized in the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic patients is somewhat decreased. In such patients, as well as in other cases of hepatic impairment, it is advisable to monitor the itraconazole plasma concentrations and to adapt the dose when necessary.
Cases of serious, usually reversible idiosyncratic hepatitis which may be fatal have been observed.
Serious hepatotoxicity, including cases of fatal acute liver failure, have occured with the use of SPORANOX. 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 heptatoxic drugs. Some patients had no obvious risk factors for liver disease. These cases have been observed within the first week of treatment up to 1½ years after continuous use of SPORANOX.
Liver function monitoring should be considered in patients receiving SPORANOX treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitus 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 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.

WARNING: Co-administration of terfenadine with itraconazole is contra-indicated. Rare cases of serious cardiovascular adverse events including death, ventricular tachycardia and torsades de pointes have been observed in patients taking itraconazole concomitantly with terfenadine, due to increased terfenadine concentrations induced by itraconazole. See CONTRA-INDICATIONS and PRECAUTIONS sections. Pharmacokinetic data indicate that another oral antifungal, ketoconazole, inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals. In vitro data suggest that itraconazole, when compared to ketoconazole, has a less pronounced effect on the biotransformation system responsible for the metabolism of astemizole. Based on the chemical resemblance of itraconazole and ketoconazole, co-administration of astemizole with itraconazole is contraindicated. See CONTRA-INDICATIONS section.

INTERACTIONS:
1. Drugs affecting the metabolism of itraconazole:
Enzyme-inducing drugs such as rifampicin, rifabutin, carbamazepine, isoniazid and phenytoin significantly reduce the bioavailability of itraconazole. Monitoring of plasma concentrations of SPORANOX is advised if these medicines are administered concomitantly. An increase in the dose of SPORANOX may be necessary.
As itraconazole is mainly metabolised through the CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of itraconazole. Examples are: ritonavir, indinavir, clarithromycin and erythromycin.
2. Effect of itraconazole on the metabolism of other drugs:
2.1 Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or prolongation of their effects, including side-effects. After stopping treatment, itraconazole plasma levels decline gradually, depending on the dose and duration of treatment. This should be taken into account when the inhibitory effect of itraconazole on comedicated drugs is considered.
Examples are:
Drugs which should 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 Contra-indications”
Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers.
Drugs whose plasma levels, effects or side-effects should be monitored. Their dosage, if co-administered with itraconazole, should be reduced if necessary.

•	Oral anticoagulants; Prothrombin time should be carefully monitored.
•	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; Patients should be monitored for side-effects, eg. oedema.
•	Certain Immunosuppressive Agents: cyclosporine, tacrolimus, rapamycin; (also known as sirolimus).
•	Others: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, ebastine, reboxetine.

Severe hypoglycaemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycaemic agents, such as tolbutamide, chlorpropamide, glyburide and glipizide. Blood glucose concentrations should be carefully monitored when SPORANOX and oral hypoglycaemic agents are co-administered.
2.2 No interaction of itraconazole with AZT (zidovudine) and fluvastatin has been observed.
No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed.
3. Effect of protein binding:
Despite the fact that SPORANOX is 99,8% bound to plasma proteins, in vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin and sulphamethazine.

PREGNANCY AND LACTATION
SPORANOX capsules should not be administered to breast feeding women.

DOSAGE AND DIRECTIONS FOR USE
SPORANOX capsules should be taken immediately after a meal for optimal absorption.
Dosage recommendations vary according to the infection treated:

Indication	Dose	Median duration
Vulvovaginal candidosis	200 mg twice daily	1 day
Dermatomycosis	200 mg daily         or 100 mg daily	7 days         or 15 days
Highly keratinized regions as in plantar tinea pedis and palmar tinea manus require 100 mg daily for 30 days, or 200 mg twice daily for 7 days
Fungal keratitis	200 mg daily	21 days
Onychomycosis Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
(continuous treatment)	200 mg daily	3 months
(pulse treatment)	200 mg twice daily	1 week Fingernail infections: 2 pulse treatments. Toenail infections: 3 pulse treatments. Pulse treatments are always separated by a 3 week drug-free interval. See table below.

Site of onychomycosis	Week 1	Weeks 2, 3 and 4	Week 5	Weeks 6, 7 and 8	Week 9
Toenails with or without fingernail involvement	Pulse 1 200 mg twice daily	itraconazole free week	Pulse 2 200 mg twice daily	itraconazole free week	Pulse 3 200 mg twice daily
Fingernails only	Pulse 1 200 mg twice daily	itraconazole free week	Pulse 2 200 mg twice daily

Elimination of itraconazole from skin and nail is slower than from plasma. Optimal clinical mycological effects are thus reached 1 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after cessation of treatment for nail infections.
Dosages that have been used in systemic mycoses:

Indication	Dose	Median duration	Remarks
Aspergillosis	200 mg daily	2 - 5 months	Increase dose to 200 mg twice daily in case of invasive or disseminated disease.
Candidiasis (excluding vulvovaginal)	100-200 mg daily	3 weeks - 7 months	Increase dose to 200 mg twice daily in case of invasive or disseminated disease.
Histoplasmosis (excluding meningeal histoplasmosis)	200 mg daily - 200 mg twice daily (or 400 mg once daily)	8 months
Sporotrichosis	100 mg daily	3 months
Paracoccidio- idomycosis	100 mg daily	6 months
Chromomycosis	100 - 200 mg daily	6 months
Blastomycosis	100 mg daily - 200 mg twice daily (or 400 mg once daily)	6 months

In children (below 12 years): SPORANOX capsules have not been systematically studied in children.
In elderly: As for use in children.
Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. The optimal dosage regimen for treatment and maintenance therapy are unknown. Studies to investigate the efficacy and safety of SPORANOX, including optimal dosage and duration in HIV-infected patients are ongoing.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
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 dermatologic origin. Within each system organ class, the adverse reactions are ranked under headings of frequency using the following convention:
Very rare (<1/10,000), including isolated reports. The following adverse events have been reported:

•	Metabolism and Nutrition Disorders
	Very rare: hypokalemia.
•	Nervous System Disorders
	Very rare: peripheral neuropathy, headache, and dizziness.
•	Cardiac Disorders
	Very rare: congestive heart failure.
•	Respiratory, Thoracic and Mediastinal Disorders
	Very rare: pulmonary oedema.
•	Gastrointestinal Disorders
	Very rare: abdominal pain, vomiting, dyspepsia, nausea, diarrhoea and constipation
•	Hepato-Biliary Disorders
	Very rare: fatal acute liver failure, serious hepatotoxicity, hepatitus, and reversible increases in hepatic enzymes
•	Skin and Subcutaneous Tissue Disorders
	Very rare: Stevens-Johnson syndrome, angio-oedema, urticaria, alopecia, rash and pruritus.
•	Reproductive System and Breast Disorders
	Very rare: menstrual disorder.
•	General Disorders and Administrative Site Conditions
	Very rare: allergic reaction, and oedema.

Less frequent cases of adrenal suppression have been reported, when high doses (600 mg/day) were given.
Precautions:

•	Itraconazole has been shown to have a negative inotropic effect and SPORANOX has been associated with reports of congestive heart failure. SPORANOX 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 (see "CONTRA-INDICATIONS" for onychomycosis). This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen, and individual risk factors for congestive heart failure. These risk factors include disease, such as ischaemic 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, SPORANOX should be discontinued.
•	Calcium channel blockers can have negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers.
•	Patients should be instructed to take SPORANOX capsules with food.
•	If neuropathy occurs that may be attributable to SPORANOX capsules, the treatment should be discontinued.
•	Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.
•	Decreased gastric acidity: Absorption is impaired when the 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 SPORANOX capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists, protonpump inhibitors) it is advisable to administer SPORANOX capsules with a cola beverage.
•	The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Monitoring of the itraconazole plasma concentrations and a dose adaptation are advisable.
•	Hepatic enzyme test values should be monitored in patients with pre-existing hepatic function abnormalities. Patients should be instructed to report any signs and symptoms that may suggest liver dysfunction so that the appropriate laboratory testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stools.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In the event of overdosage, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. No specific antidote is available.
Itraconazole cannot be removed by haemodialysis.

IDENTIFICATION
Pink and blue capsules containing white to faintly cream-coloured beads (pellets).

PRESENTATION
Carton containing one or more blister strips of 4, 5 or 7 capsules each.

STORAGE CONDITIONS
Store below 25°C in a dry place. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
W/20.2.2/43

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN –CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No 1980/011122/07)
15th Road
HALFWAY HOUSE
1685
www.janssencilag.co.za

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
August 2003

An Afrikaans version of the package insert will be made available, on request.

                        024505 2003I
                        Britepak

Updated on this site: April 2004
Current: April 2005
Source: Pharmaceutical Industry
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