Sporanox Capsules (Itraconazole)

SPORANOX® Capsules Janssen-Ortho Itraconazole Antifungal

In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol which is a vital component of fungal and yeast cell membranes. This inhibition leads to deteriorated membranes, disturbed enzyme activities and an uncoordinated synthesis of chitin, all together contributing to the antifungal activity. The inhibition of ergosterol synthesis has been attributed to interference with the reactions involved in the removal of the 14-a-methyl group of the precursor of ergosterol, lanosterol. Itraconazole has a very low affinity for mammalian P450 enzymes in contrast to fungal P450 enzymes. Itraconazole is fungitoxic to dermatophytes and yeasts.

Indications and Clinical Uses:

For the treatment of the following fungal infections in normal, predisposed or immunocompromised patients: dermatomycoses due to tinea corporis, tinea cruris, tinea pedis and pityriasis versicolor, where oral therapy is considered appropriate; onychomycosis; invasive and noninvasive pulmonary aspergillosis; oral and oral/esophageal candidiasis; chronic pulmonary histoplasmosis; cutaneous and lymphatic sporotrichosis; paracoccidioidomycosis; chromomycosis; blastomycosis.

The type of organism responsible for the infection should be isolated and identified and other relevant laboratory studies (wet mount, histopathology, serology) should be undertaken, as appropriate, to confirm diagnosis. Therapy may be initiated prior to obtaining these results when clinically warranted; however, once these results become available, antifungal therapy should be adjusted accordingly.

Since elimination of itraconazole from skin and nail tissues is slower than from plasma, optimal clinical and mycological responses are 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.

Contra-Indications:

Concurrent therapy of terfenadine with itraconazole is contraindicated. 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.

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, coadministration of astemizole with itraconazole is contraindicated.

Concomitant administration of cisapride with oral ketoconazole is contraindicated because it has resulted in markedly elevated cisapride plasma concentrations and prolonged QT intervals, and has rarely been associated with ventricular arrhythmia and torsades de pointes. Due to potent in vitro inhibition of the hepatic enzyme system mainly responsible for the metabolism of cisapride (cytochrome P450 3A4), itraconazole is also expected to markedly raise cisapride plasma concentrations. Therefore, concomitant use of cisapride with itraconazole is also contraindicated.

Oral midazolam and triazolam should not be used by patients during treatment with itraconazole capsules. Pharmacokinetic data revealed higher and prolonged midazolam concentrations when oral midazolam was administered concomitantly with itraconazole versus placebo. A more pronounced and prolonged hypnotic effect of midazolam was also observed. Metabolism of both itraconazole and midazolam by the same cytochrome P450 3A isozyme may explain this interaction. Similar pharmacokinetic and pharmacodynamic effects have been observed for triazolam which is primarily metabolized by the same P450 3A isozyme (see Precautions, Drug Interactions).

Itraconazole inhibits the metabolism of HMG-CoA reductase inhibitors such as lovastatin. Coadministration of itraconazole and lovastatin resulted in elevated and prolonged plasma concentrations of lovastatin and its active metabolite, lovastatin acid, which may increase the risk of diffuse myalgia and rhabdomyolysis. Therefore, HMG-CoA reductase inhibitors that are metabolized by the P450 3A enzyme system, such as lovastatin, should not be used during treatment with itraconazole.

Itraconazole is contraindicated in patients with known hypersensitivity to the drug or its excipients. 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.

Pregnancy: Itraconazole should not be administered for the treatment of dermatomycoses (tinea corporis, tinea cruris, tinea pedis, pityriasis versicolor) to pregnant patients or to women contemplating pregnancy.

Warnings in Clinical States:

During long-term therapy in patients, most of whom had major underlying pathology and multiple concomitant treatments, a few cases of hepatitis have been observed. Itraconazole is predominantly metabolized in the liver. For therapy longer than 30 days, liver function should be monitored by appropriate tests. Patients who develop abnormal liver function tests during itraconazole therapy should be monitored for the development of more severe hepatic injury. Although serious hepatic reactions have been rare and the causal relationship with itraconazole uncertain, if clinical signs and symptoms consistent with liver disease develop during itraconazole therapy, administration of itraconazole should be discontinued and the potential cause of the liver disease should be investigated. It is not advisable to give this drug to patients with a known history of liver disease or to patients who have experienced liver toxicity with other drugs.

Women of Childbearing Age: In women of childbearing potential, an effective form of contraception must be used during therapy and for 1 menstrual cycle (1 month) after stopping therapy with itraconazole.

Pregnancy: Itraconazole has been shown to produce teratogenic effects (major skeletal and secondary soft tissue defects) when administered at high doses (40 mg/kg/day or higher) to pregnant rats. When administered to pregnant mice at high doses (80 mg/kg/day or higher) itraconazole has been shown to produce encephaloceles and/or macroglossia. There are no studies available on the use of itraconazole in pregnant women; therefore, itraconazole should be used in pregnancy only if the benefit outweighs the potential risk. Itraconazole should not be used for the treatment of dermatomycoses in pregnant patients or in women contemplating pregnancy (see Contraindications).

Lactation: Itraconazole is excreted in human milk; therefore, the patient should be advised to discontinue nursing while taking itraconazole.

Precautions:

General: Patients should be instructed to report any signs and symptoms which may suggest liver dysfunction so that appropriate biochemical testing can be done. Such signs and symptoms would include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stools. Patients who receive itraconazole concomitantly with potentially hepatotoxic drugs, those who are expected to be on long-term (>30 days) therapy, as well as those with a history of significant alcohol intake or suspicion of liver disorder should have liver function monitored (see Warnings).

Patients should be instructed to take itraconazole with food.

Patients with Decreased Gastric Acidity: Absorption of itraconazole is impaired when gastric acidity is decreased. In patients also receiving acid-neutralizing medicines (e.g., aluminum hydroxide), these should be administered at least 2 hours after the intake of itraconazole. In patients with achlorhydria, such as certain AIDS patients on acid secretion suppressors (e.g., H 2-antagonists, proton pump inhibitors), it is advisable to administer itraconazole with a cola beverage.

Children: The efficacy and safety of itraconazole have not been established in children. No pharmacokinetic data are available in children. A small number of patients from age 3 to 16 years have been treated with 100 mg/day of itraconazole for systemic fungal infections and no serious adverse effects have been reported.

Toxicological studies have shown that itraconazole, when administered to rats, can produce bone toxicity. While no such toxicity has been reported in adult patients, the long-term effect of itraconazole in children is unknown.

Geriatrics: The pharmacokinetics of itraconazole after single and repeated dosing of 100 mg once daily in 12 elderly subjects were found to be similar to those in young and middle-aged adults. Therefore, no dose adjustments are required in elderly patients.

Patients with Hepatic Impairment: Itraconazole is predominantly metabolized in the liver. The oral bioavailability in cirrhotic patients is somewhat decreased. It is advisable to monitor itraconazole plasma concentrations and to adapt the dose when necessary (see also Warnings and Precautions [General]).

Patients with Renal Insufficiency: The absorption of itraconazole may be lower in patients with renal insufficiency. Since clinical experience is lacking in this patient population, dosage recommendations cannot be made at this time.

In a few patients, hypokalemia has been reported. Consequently, serum potassium should be monitored in patients at risk during high-dose itraconazole therapy.

Itraconazole cannot be removed by dialysis.

Acquired Immunodeficiency Syndrome (AIDS) and Neutropenic Patients: Studies with itraconazole in neutropenic and AIDS patients have indicated that itraconazole plasma concentrations are lower than those in healthy subjects (particularly in those patients who are achlorhydric); therefore, monitoring of the itraconazole plasma concentrations and a dose adjustment, if necessary, is recommended. In 1 study, adequate plasma concentrations of itraconazole (measured by HPLC) for antifungal prophylaxis in neutropenic patients were greater than 250 ng/mL.

Inadequate plasma concentrations were frequently found in patients whose antineoplastic therapy predisposed them to very poor oral absorption and frequent vomiting. In this case, antiemetics can be coadministered and it is particularly important that itraconazole be administered with meals.

There has been 1 report of reduced itraconazole absorption when taken with didanosine. Since the excipients in the didanosine formulation are known to have an acid-neutralizing effect, and since the absorption of itraconazole can be affected by the level of acidity in the stomach, it is recommended that didanosine be administered at least 2 hours after dosing with itraconazole.

The results from a study in which 8 HIV-infected individuals were treated with zidovudine, 8±0.4 mg/kg/day, with or without itraconazole, 100 mg b.i.d., showed that the pharmacokinetics of zidovudine were not affected during concomitant administration of itraconazole.

Drug Interactions:

Itraconazole can inhibit the metabolism of drugs metabolized by the cytochrome 3A family. This can result in an increase and/or prolongation of their effects:

Concurrent therapy of terfenadine with itraconazole has led to elevated plasma concentrations of terfenadine, resulting in rare instances of life-threatening cardiac dysrhythmias and 1 death (see Contraindications).

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, concurrent therapy of astemizole with itraconazole is contraindicated (see Contraindications).

Human pharmacokinetic data indicate that oral ketoconazole potently inhibits the metabolism of cisapride, resulting in a mean 8-fold increase in AUC of cisapride. Data suggest that coadministration of cisapride and oral ketoconazole can result in prolongation of the QT interval on the ECG. In vitro data suggest that itraconazole also markedly inhibits the biotransformation system mainly responsible for the metabolism of cisapride. Therefore, concomitant administration of itraconazole with cisapride is contraindicated (see Contraindications).

Pharmacokinetic data demonstrate that when coadministered, itraconazole inhibits the metabolism of lovastatin, resulting in increased plasma concentrations of lovastatin, and its active metabolite lovastatin acid, and a 20-fold increase in AUC for both compounds. These increased plasma levels potentially elevate the risk of skeletal muscle toxicity such as diffuse myalgia and rhabdomyolysis. Therefore, concomitant administration of itraconazole with HMG-CoA reductase inhibitors such as lovastatin is contraindicated (see Contraindications).

Pharmacokinetic data suggest that itraconazole may inhibit the metabolism of oral midazolam. In 9 subjects, pretreatment with 200 mg itraconazole once daily for 4 days resulted in a 10-fold increase in midazolam AUC 0®¥, an approximate 3-fold increase in C max, and an approximate 3-fold increase in t 1/2. Enhanced and prolonged sedative effects were also observed. Similar pharmacokinetic and pharmacodynamic effects have been observed for triazolam which is primarily metabolized by the same P450 3A isozyme. In 9 subjects, pretreatment with 200 mg itraconazole for 4 days resulted in a 27-fold increase in triazolam AUC 0®¥, a 3-fold increase in C max and a 7-fold increase in t 1/2. Midazolam and triazolam should not be used by patients during treatment with itraconazole (see Contraindications). If midazolam is administered i.v., special precaution is required since the sedative effect may be prolonged.

Concurrent therapy of itraconazole and cyclosporine or digoxin has led to increased plasma concentrations of the latter two drugs. When digoxin is given concurrently with itraconazole, the physician is advised to monitor digoxin concentrations and reduce the dosage as needed. Although no studies have been conducted, literature case reports suggest that the dose of cyclosporine should be reduced by 50% when itraconazole doses greater than 100 mg daily are given. Cyclosporine concentrations should be monitored frequently and the dose adjusted appropriately.

Itraconazole may inhibit the metabolism of methylprednisolone, vinca alkaloids and possibly tacrolimus. The dosage of systemic methylprednisolone, vinca alkaloids and tacrolimus, if coadministered with itraconazole, should be reduced if necessary.

It has been reported that itraconazole enhances the anticoagulant effect of coumarin-like drugs. Therefore, prothrombin time should be carefully monitored in patients receiving itraconazole and coumarin-like drugs simultaneously.

Patients receiving itraconazole concomitantly with dihydropyridine calcium channel blockers or quinidine, should be monitored for side effects, e.g., edema and tinnitus/decreased hearing, respectively. If necessary, the dose of these drugs should be reduced.

When itraconazole was coadministered with phenytoin, rifampin or H 2 antagonists, reduced plasma concentrations of itraconazole were reported. The physician is advised to monitor the plasma concentrations of itraconazole when any of these drugs is taken concurrently, and to increase the dose of itraconazole if necessary. Although no studies have been conducted, concomitant administration of itraconazole and phenytoin may alter the metabolism of phenytoin; therefore, plasma concentrations of phenytoin should also be monitored when it is given concurrently with itraconazole.

Plasma concentrations of azole antifungal agents are reduced when given concurrently with isoniazid. Itraconazole plasma concentrations should be monitored when itraconazole and isoniazid are coadministered.

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when itraconazole and oral hypoglycemic agents are coadministered.

There has been 1 report of reduced itraconazole absorption when taken with didanosine. Since the excipients in the didanosine formulation are known to have an acid-neutralizing effect, and since the absorption of itraconazole can be affected by the level of acidity in the stomach, it is recommended that didanosine be administered at least 2 hours after dosing with itraconazole (see AIDS and Neutropenic Patients).

No interaction of itraconazole with AZT (zidovudine) has been observed (see AIDS and Neutropenic Patients).

No inducing effects of itraconazole on the metabolism of ethinylestradiol and norethisterone were observed.

Laboratory Tests: Plasma levels 3 to 4 hours after dosing with itraconazole should be monitored in patients requiring treatment for more than 1 month, in patients with systemic mycoses who have factors predisposing to poor absorption (such as achlorhydria, renal insufficiency, neutropenia, AIDS) or in those who are taking drugs which may alter itraconazole absorption or metabolism (such as rifampin and phenytoin).

Due to the presence of an active metabolite, monitoring of plasma levels by bioassay will indicate plasma levels roughly 3 times higher than will monitoring by high-pressure liquid chromatography, unless solvent conditions for the HPLC assay are adjusted to allow simultaneous detection of both the parent drug and this metabolite (hydroxy-itraconazole).

Adverse Reactions:

Adverse experiences during short-term therapy with itraconazole occurred in 7.8% of patients. During long-term therapy in patients, most of whom had underlying pathology and received multiple concomitant treatments, the incidence of adverse experiences was higher (20.6%). The most common adverse experiences (reported by at least 1% of patients) during short-term or long-term therapy with itraconazole:

Adverse Reactions:

Short-term Therapy Long-term Therapy

Total Number of Patients 12 889 916

Body System/ Adverse Event Incidence (%)

Gastrointestinal 4.4 9.1

nausea 1.6 2.9

Dermatological 0.8 4.5

rash <1.0 1.6

pruritus <1.0 1.3

CNS 2.1 4.3

headache 1.0 1.1

Respiratory System <1.0 3.9

Liver and Biliary System 0.11 2.7

Miscellaneous 0.7 5.6

edema <1.0 1.0

For 834 clinical trial patients receiving 2 to 4 cycles of 1 week therapy, the most frequently reported adverse events during the treatment and follow-up period were: abdominal pain (1.9%), nausea (1.6%) and headache (1.3%).

The following adverse experiences have been reported at an incidence greater than 0.05% and less than 1% during short-term therapy with itraconazole: dyspepsia/epigastric pain/upset stomach; abdominal pain/discomfort; vomiting; pyrosis; diarrhea; gastritis; flatulence/meteorism; constipation; decreased appetite; other gastric complaints; dizziness/faintness; sleepiness/somnolence; vertigo; pruritus; rash; pain; fatigue; fever; edema; allergic reaction. Allergic reactions (such as pruritus, rash, urticaria and angioedema) and reversible increases in hepatic enzymes, and menstrual disorder have been reported from postmarketing experience. Isolated cases of peripheral neuropathy and of Stevens-Johnson syndrome have been reported; a causality for the latter has not been established. If neuropathy occurs that may be attributable to itraconazole, the treatment should be discontinued.

The following adverse experiences have been reported at an incidence of greater than 0.5% but less than 1% of patients during long-term therapy with itraconazole: vomiting; dyspepsia/epigastralgia; diarrhea; abdominal pain; dizziness; bronchitis/bronchospasm; coughing; dyspnea; rhinitis; sinusitis; increase in liver enzymes; abnormal liver function tests; jaundice; hepatitis; cirrhosis; hepatocellular damage; abnormal hepatic function; pain; chest pain; hypertension; fatigue; fever; hypokalemia.

Postmarketing: Especially in patients receiving prolonged (approx. 1 month) treatment, most of whom had major underlying pathology and multiple concomitant medications, cases of hypokalemia, edema, hepatitis and hair loss have been observed.

Symptoms And Treatment Of Overdose:

There is no experience of overdosage with itraconazole; however, based on animal toxicity data, symptoms of a gastrointestinal or CNS nature may be expected to occur.

In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. It has been reported that itraconazole cannot be removed by hemodialysis.

Dosage And Administration:

When itraconazole therapy may be indicated, the type of organism responsible for the infection should be isolated and identified; however, therapy may be initiated prior to obtaining these results, when clinically warranted. For maximal absorption, it is essential to administer itraconazole immediately after a full meal. The capsules must be swallowed whole. For treatment of patients with decreased gastric acidity, see Precautions.

Itraconazole should be administered at a dose of 100 to 400 mg/day. Dosage recommendations vary according to the infection treated.

Oral and Oral/Esophageal Candidiasis: The recommended dose is 100 mg daily for 2 weeks. The dose should be increased to 200 mg/day in patients with AIDS and neutropenic patients. In patients with oral/esophageal candidiasis, treatment should last 4 weeks.

Blastomycosis and Chronic Pulmonary Histoplasmosis: The recommended dose is 200 mg once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, the dose should be increased in 100 mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in 2 divided doses.

Treatment should be continued for a minimum of 3 months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.

Equivalency between standard and alternative dosages was not established. Patients with chronic recalcitrant tinea pedis may benefit from the standard dosage of lower daily dose (100 mg) for a longer period of time (4 weeks).

Onychomycosis: The recommended clinical dose for onychomycosis is: A 1-week treatment course consists of 200 mg twice daily for 7 days. Treatment with two 1-week courses is recommended for fingernail infections and three 1-week courses for toenail infections. The 1-week courses are always separated by a 3-week drug-free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.

Toenails with or without fingernail involvement 200 mg b.i.d. for 7 days itraconazole free weeks 200 mg b.i.d. for 7 days itraconazole free weeks 200 mg b.i.d. for 7 days

Fingernails only 200 mg b.i.d. for 7 days itraconazole free weeks 200 mg b.i.d. for 7 days

Tissue Elimination of Itraconazole: Elimination of itraconazole from skin and nail tissues is slower than from plasma. Optimal clinical and mycological responses are 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.

Availability And Storage:

Each pink and blue capsule, imprinted in white with JANSSEN on the cap and SPORANOX100 on the body, contains: itraconazole 100 mg in a pellet formulation. Nonmedicinal ingredients: D&C Red No. 22, D&C Red No. 28, FD&C Blue No. 1, FD&C Blue No. 2, gelatin, hydroxypropylmethylcellulose, polyethylene glycol, sugar spheres and titanium dioxide. Bisulfite-, gluten- and tartrazine-free. HDPE bottles of 30 and Pulsepak cartons of 7 blister cards containing 4 capsules. The Pulsepak is specifically designed for use in the treatment of onychomycosis. Store at room temperature (15 to 30°C). Protect from light and moisture.

SPORANOX® Capsules Janssen-Ortho Itraconazole Antifungal

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