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Itraconazole
SporanoxTM capsule
Description
Itraconazole (SporanoxTM) is a synthetic broad-spectrum antifungal agent available as pink and blue capsules containing 100 mg itraconazole in a pellet formulation for oral administration.
The other ingredients are sugar spheres, hypromellose and macrogol (formulation F78).
The capsule itself contains titanium dioxide, indigotindisulphonate sodium, erythrosine sodium and gelatin.
Properties
Pharmacodynamics
Itraconazole, a triazole derivative, is active against infections with dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum spp., Candida spp., including C.albicans, C. glabrata and C. krusei), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, and various other yeasts and fungi.
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.
Pharmacokinetics
The oral bioavailability of itraconazole is maximal when the capsules are taken immediately after a full meal. Peak plasma levels are reached 3 to 4 hours following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1 to 1.5 days. 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 µg/mL (100 mg o.d.), 1.1 µg/mL (200 mg o.d.) and 2.0 µg/mL (200 mg b.i.d.).
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 to 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 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 b.i.d.
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. Fecal 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 a dose is excreted as metabolites in the urine within 1 week.
Therapeutic indications
Itraconazole (SporanoxTM) capsule is indicated for the treatment of the following conditions:
Gynecological indications: Vulvovaginal candidosis.
Dermatological/ophthalmological indications:
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.
Contraindications
Itraconazole (SporanoxTM) capsule is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
Itraconazole (SporanoxTM) capsules 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 fetus. Adequate contraceptive precautions should be taken by women of childbearing potential using itraconazole (SporanoxTM) capsules until the next menstrual period following the end of itraconazole (SporanoxTM) therapy.
Terfenadine, astemizole, cisapride, quinidine, pimozide, CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin and lovastatin, triazolam and oral midazolam are contra-indicated with itraconazole (SporanoxTM) capsules.
Special warnings and special precautions for use
Itraconazole (SporanoxTM) has a potential for clinically important drug interactions. (See Interactions).
Decreased gastric acidity: Absorption of itraconazole from SporanoxTM capsules is impaired when the gastric acidity is decreased. In patients also receiving acid neutralizing medicines (e.g. aluminium hydroxide) these should be administered at least 2 hours after the intake of itraconazole (SporanoxTM) 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 (SporanoxTM) capsules with a cola beverage.
Pediatric use: Since clinical data on the use of itraconazole (SporanoxTM) capsules in pediatric patients is limited, itraconazole (SporanoxTM) capsules should not be used in these patients unless the potential benefit outweighs the potential risks.
It is advisable to monitor liver function in patients receiving continuous treatment of more than one month and promptly in patients developing symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. If abnormal, treatment should be stopped. In patients with raised liver enzymes or an 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 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. 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 itraconazole (SporanoxTM) capsules, the treatment should be discontinued.
There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing itraconazole (SporanoxTM) capsules to patients with hypersensitivity to other azoles.
Interactions
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, such as carbamazepine, phenobarbital and isoniazid, but similar effects should be anticipated.
As itraconazole is mainly metabolized through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of itraconazole. Examples are: ritonavir, indinavir and clarithromycin.
Effect of itraconazole on the metabolism of other drugs:
Itraconazole can inhibit the metabolism of drugs metabolized by the cytochrome 3A family. 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 Pharmacokinetics). 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, cisapride, triazolam, oral midazolam, quinidine, pimozide, CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin and lovastatin.
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 such as ritonavir, indinavir, saquinavir;
Certain Antineoplastic Agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate;
CYP3A4 metabolized Calcium Channel Blockers such as dihydropyridines and verapamil;
Certain Immunosuppressive Agents: cyclosporine, tacrolimus, rapamycin;
Others: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, midazolam IV, rifabutin, methylprednisolone.
No interaction of itraconazole with AZT (zidovudine) and fluvastatine has been observed.
No inducing effects of itraconazole on the metabolism of ethinylestradiol 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, indomethacin, tolbutamide and sulfamethazine.
Pregnancy and lactation
When administered at high doses to pregnant rats (40 mg/kg/day or higher) and mice (80 mg/kg/day or higher), itraconazole was shown to increase the incidence of fetal abnormalities and did produce adverse effects on the embryo. Studies of the use of itraconazole in pregnant women are not available. Therefore, itraconazole (SporanoxTM) capsules 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 fetus.
A very small amount of itraconazole is excreted in human milk. The expected benefits of itraconazole (SporanoxTM) capsules therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt the patient should not breast-feed.
Effects on driving ability and use of machinery
No effects have been observed.
Dosage and administration
For optimal absorption, it is essential to administer itraconazole (SporanoxTM) capsules immediately after a full meal.
The capsules must be swallowed whole.
Indication |
Dose |
Duration |
Gynecological indications
Vulvovaginal candidosis |
200 mg b.i.d.
or 200 mg o.d. |
1 day
3 days |
Dermatological/ ophthalmological
indications:
Pityriasis versicolor |
200 mg o.d. |
7 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 o.d. |
15 days |
In some immunocompromised patients, e.g. neutropenic, AIDS or organ transplant patients, the oral bioavailability of itraconazole may be decreased. Therefore, the doses may need doubling. |
| Fungal keratitis |
200 mg o.d. |
21 days |
- Onychomycosis
pulse treatment (see table below):
A pulse treatment consists of two capsules twice daily (200 mg BID) for one 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.
Site of
onychomycosis |
Wk
1 |
Wk
2 |
Wk
3 |
Wk
4 |
Toenails with or without fingernail involvement |
Pulse 1 |
itraconazole free weeks |
Fingernails only |
Pulse 1 |
itraconazole free weeks |
Site of
onychomycosis |
Wk
5 |
Wk
6 |
Wk
7 |
Wk
8 |
Wk
9 |
Toenails with or without fingernail involvement |
Pulse 2 |
itraconazole free weeks |
Pulse 3 |
Fingernails only |
Pulse 2 |
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OR
Elimination of itraconazole from skin and nail tissue is slower than from plasma. Optimal clinical and mycological response is thus reached 2 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after the cessation of treatment for nail infections.
Indication |
Dose |
Median duration |
Remarks |
Aspergillosis Candidosis |
200 mg o.d. 100-200 mg o.d. |
2-5 months 3 weeks-7 months |
Increase dose to
200 mg b.i.d. in
case of invasive or
disseminated
disease
|
Non-meningeal
cryptococcosis
Cryptococcal
Meningitis |
200 mg o.d. 200 mg b.i.d. |
2 months-1 year |
Maintenance
therapy:
(meningeal
cases)
200 mg o.d. |
Histoplasmosis
Sporotrichosis
Paracoccidioido-
mycosis
Chromomycosis
Blastomycosis |
200 mg o.d. -
200 mg b.i.d.
100 mg o.d.
100 mg o.d.
100-200 mg o.d.
100 mg o.d. -
200 mg b.i.d. |
8 months
3 months
6 months
6 months
6 months |
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Undesirable effects
The most frequently reported adverse experiences in association with the use of itraconazole (SporanoxTM) capsules were of gastro-intestinal origin, such as dyspepsia, nausea, abdominal pain and constipation. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorder, dizziness and allergic reactions (such as pruritus, rash, urticaria and angio-edema). 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 hypokalemia, edema, hepatitis and hair loss have been observed.
Overdosage
No data are available.
In the event of accidental 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.
Itraconazole cannot be removed by hemodialysis.
No specific antidote is available.
How supplied
Supplied in blister packs of 100 caps/box.
Storage conditions
Store between 15 and 30°C.
Keep out of reach of children.
CAUTION: Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
Manufactured by:
INTERPHIL LABORATORIES, INC.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
for Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque, Metro Manila
Under license from:
JANSSEN PHARMACEUTICA
Beerse, Belgium
Exclusively distributed by:
ZUELLIG PHARMA CORPORATION
Sen. Gil Puyat Avenue
Makati City
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