The inactive ingredients of the capsule are sugar spheres, hypromellose and macrogol. The capsule itself contains titanium dioxide, indigotindisulfonate sodium, erythrosine sodium and gelatin.
Itraconazole is a synthetic broad-spectrum antifungal agent.
In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
Microbiology: Itraconazole, a triazole derivative, is active against infections with dermatophytes (Trichophyton and Microsporum spp, Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum and Candida spp, including C. albicans, C. glabrata and C. krusei), Aspergillus and Histoplasma spp, Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea and Cladosporium spp, Blastomyces dermatitidis, and various other yeasts and fungi.
Pharmacokinetics: The oral bioavailability of itraconazole is maximal when the capsules are taken immediately after a full meal. Peak plasma levels are reached 3-4 hrs following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1-1.5 days. During chronic administration, steady-state is reached after 1-2 weeks. Steady-state plasma concentrations of itraconazole 3-4 hrs after drug intake are 0.4 mcg/mL (100 mg once daily), 1.1 mcg/mL (200 mg once daily) and 2 mcg/mL (200 mg twice daily).
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 4 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 2-4 weeks after discontinuation of a 4-week treatment. Levels of itraconazole have been detected in the nail keratin as early as 1 week after start of treatment and 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.
Itraconazole is also extensively distributed into tissues that are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2-3 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 2 times a day.
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 bioassay 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 <0.03% of the dose. About 35% of the dose is excreted as metabolites in the urine within 1 week.
Treatment of the following conditions:
Gynaecological: Vulvovaginal candidosis.
Dermatological/Ophthalmological: Pityriasis versicolor, dermatomycosis, fungal keratitis and oral candidosis. Onychomycosis, caused by dermatophytes and/or yeasts.
Systemic Mycoses: Systemic aspergillosis and candidosis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis, and other rarely occurring systemic or tropical mycoses.
For optimal absorption, it is essential to administer Sporanox immediately after a full meal. The capsules must be swallowed whole.
Gynaecological:
Vulvovaginal Candidosis: 200 mg twice daily for 1 day or 200 mg once daily for 3 days.
Dermatological/Ophthalmological:
Pityriasis versicolor: 200 mg once daily for 7 days.
Dermatomycosis: 200 mg once daily for 7 days or 100 mg daily for 15 days.
Highly keratinized regions as in plantar tinea pedis and palmar tinea manus require 200 mg twice daily for 7 days, or 100 mg daily for 30 days.
Oral Candidosis: 100 mg once daily for 15 days.
In some immunocompromised patients eg, neutropenic, AIDS or organ transplant patients, the oral bioavailability of itraconazole may be decreased. Therefore, the doses may need doubling.
Fungal Keratitis: 200 mg once daily for 21 days.
Onychomycosis: Pulse treatment (see table).
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A pulse treatment consists of 2 caps twice daily (200 mg twice daily) for 1 week. Two pulse treatments are recommended for fingernail infections, and three pulse treatments for toenail infections. Pulse treatments are always separated by a 3-week drug-free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.
Continuous Treatment: 2 caps daily (200 mg once daily) for 3 months.
Elimination of Sporanox from skin and nail tissue is slower than from plasma. Optimal clinical and mycological response is thus reached 2-4 weeks after the cessation of treatment for skin infections and 6-9 months after the cessation of treatment for nail infections.
Systemic Mycoses (Dosage recommendations vary according to the infection treated):
Aspergillosis: 200 mg once daily for 2-5 months.
Candidosis: 100-200 mg once daily for 3 weeks to 7 months.
For both aspergillosis and candidosis, increase dose to 200 mg twice daily in case of invasive or disseminated disease.
Non-Meningeal Cryptococcosis: 200 mg once daily for 2 months to 1 year.
Cryptococcal Meningitis: 200 mg twice daily for 2 months to 1 year.
Maintenance Therapy (Meningeal Cases): 200 mg once daily.
Histoplasmosis: 200 mg once daily or 200 mg twice daily for 8 months.
Sporotrichosis: 100 mg once daily for 3 months.
Paracoccidioidomycosis: 100 mg once daily for 6 months.
Chromomycosis: 100-200 mg once daily for 6 months.
Blastomycosis: 100 mg once daily or 200 mg twice daily for 6 months.
No data are available. In the event of accidental overdosage, supportive measures should be employed.
Within the 1st hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate.
Itraconazole cannot be removed by haemodialysis.
No specific antidote is available.
Patients who have known hypersensitivity to Sporanox or its excipients.
Sporanox should only be given to pregnant women in life-threatening cases and when in these cases, the potential benefit outweighs the potential harm to the foetus. Adequate contraceptive precautions should be taken by women of childbearing potential using Sporanox until the next menstrual period following the end of Sporanox therapy.
Terfenadine, astemizole, mizolastine, cisapride, difetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors eg, simvastatin and lovastatin, triazolam and oral midazolam are cotraindicated with Sporanox capsules.
Sporanox has a potential for clinically important drug interactions (see Interactions).
In a healthy volunteer study with Sporanox 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 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. This individual benefit/risk assessment should take into consideration factors eg, the severity of the indication, the dosing regimen and individual risk factors for congestive heart failure. These risk factors include cardiac disease eg, ischemic and valvular disease; significant pulmonary disease eg, 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 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.
Decreased Gastric Acidity: Absorption of itraconazole from Sporanox is impaired when the gastric acidity is decreased. In patients also receiving acid neutralising medicines (eg, aluminum hydroxide), these should be administered at least 2 hrs after the intake of Sporanox. In patients with achlorhydria eg, certain AIDS patients and patients on acid secretion supressors (eg, H2-antagonists, proton-pump inhibitors), it is advisable to administer Sporanox with a cola beverage.
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox. Most of these cases involved patients who had preexisting 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 have been observed within the 1st month of treatment, including some within the 1st week. 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 hepatitis eg, 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.
Hepatic Impairment: Itraconazole is predominantly metabolised in the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic patients is somewhat decreased. A dose adjustment may be considered.
Renal Impairment: The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. A dose adjustment may be considered.
If neuropathy occurs that may be attributable to Sporanox, the treatment should be discontinued.
There is no information regarding the cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Sporanox to patients with hypersensitivity to other azoles.
Effects on the Ability to Drive or Operate Machinery: No effects have been observed.
Use in pregnancy & lactation: When administered at high doses to pregnant rats (≥40 mg/kg/day) and mice (≥80 mg/kg/day), itraconazole was shown to increase the incidence of foetal abnormalities and did produce adverse effects on the embryo. Studies of the use of itraconazole in pregnant women are not available. Therefore, Sporanox should only be given in life-threatening cases of systemic mycosis and when in these cases, the potential benefit outweighs the potential harm to the foetus.
A very small amount of itraconazole is excreted in human milk. The expected benefits of Sporanox therapy should therefore be weighed against the potential risk of breastfeeding. In case of doubt, the patient should not breastfeed.
Use in children: Since clinical data of the use of Sporanox in paediatric patients is limited, Sporanox should not be used in these patients unless the potential benefit outweighs the potential risks.
When administered at high doses to pregnant rats (≥40 mg/kg/day) and mice (≥80 mg/kg/day), itraconazole was shown to increase the incidence of foetal abnormalities and did produce adverse effects on the embryo. Studies of the use of itraconazole in pregnant women are not available. Therefore, Sporanox should only be given in life-threatening cases of systemic mycosis and when in these cases, the potential benefit outweighs the potential harm to the foetus.
A very small amount of itraconazole is excreted in human milk. The expected benefits of Sporanox therapy should therefore be weighed against the potential risk of breastfeeding. In case of doubt, the patient should not breastfeed.
The most frequently reported adverse experiences in association with the use of Sporanox were of gastrointestinal origin eg, dyspepsia, nausea, abdominal pain and constipation. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorder, dizziness and allergic reactions (eg, pruritus, rash, urticaria and angio-oedema). Isolated cases of peripheral neuropathy and of Stevens-Johnson syndrome have also been reported.
Especially in patients receiving prolonged (approximately 1 month) continuous treatment, cases of hypokalaemia, oedema, hepatitis and hair loss have been observed.
Drugs Affecting the Metabolism of Itraconazole: Interaction studies have been performed with rifampicin, rifabutin and phenytoin. 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 eg, 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 eg, ritonavir, indinavir, clarithromycin and erythromycin.
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 prolongation of their effects, including side effects. After stopping treatment, itraconazole plasma levels decline gradually, depending on the dose and duration of treatment (see Pharmacokinetics under Actions). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered.
Drugs which should not be used during treatment with itraconazole: Terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, difetilide, quinidine, pimozide. CYP3A4 metabolised HMG-CoA reductase inhibitors eg, simvastatin and lovastatin.
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; HIV protease inhibitors eg, ritonavir, indinavir, saquinavir; certain antineoplastic agents eg, vinca alkaloids, busulphan, docetaxel and trimetrexate; CYP3A4 metabolised calcium-channel blockers eg, dihydropyridines and verapamil; certain immunosuppressive agents eg, cyclosporine, tacrolimus, rapamycin; others eg, digoxin, carbamazepine, buspirone, alfentanil, alprazolam, midazolam IV, rifabutin, methylprednisolone.
No interaction of itraconazole with zidovudine (AZT) and fluvastatine has been observed.
No inducing effects of itraconazole on the metabolism of ethinylestradiol and norethisterone were observed.
Effects 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 and sulfamethazine.
Store between 15°C and 30°C.
J02AC02 - itraconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.
Sporanox Capsule cap 100 mg
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