Sporanox (Itraconazole Capsules)

SPORANOX® Oral Solution Janssen-Ortho Itraconazole Antifungal

Action and Clinical

Mode of Action: Itraconazole, a triazole derivative, has a broad-spectrum activity; with respect to Candida spp., its activity includes C. albicans, C. glabrata and C. krusei.

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 oral solution is maximal when it is taken without food. During chronic administration, steady-state is reached after 1 to 2 weeks. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following the oral administration. After repeated once-a-day administration of itraconazole 200 mg in fasting condition, steady-state plasma concentrations of itraconazole fluctuate between 1 and 2 g/mL (trough to peak). When the oral solution is taken with food, steady-state plasma concentrations of itraconazole are about 25% lower.

The plasma protein binding of itraconazole is 99.8%. Itraconazole is extensively distributed into tissues which are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2 to 3 times higher than the corresponding plasma concentration.

Itraconazole is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole, which has in vitro a comparable antifungal activity to itraconazole. Plasma levels of hydroxy-itraconazole are about 2 times higher than those of itraconazole.

After repeated oral administration, elimination of itraconazole from plasma is biphasic with a terminal half-life of 1.5 days. Fecal excretion of the parent drug varies between 3 to 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 1 week.

Indications And Clinical Uses:

For the treatment of oral and/or esophageal candidiasis in adult HIV-positive or other immunocompromised patients.

Note: Itraconazole oral solution and itraconazole capsules should not be used interchangeably.

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.

Coadministration of astemizole with itraconazole has led to elevated plasma concentrations of astemizole and its active metabolite desmethylastemizole which may prolong the QT intervals. Therefore, concomitant administration of itraconazole with astemizole is contraindicated.

Concomitant administration of cisapride with oral ketoconazole is contraindicated because it has resulted in markedly elevated cisapride plasma concentrations and prolonged QT interval, 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. 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.

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.

Warnings in Clinical States:

Itraconazole oral solution and itraconazole capsules should not be used interchangeably. Itraconazole oral solution has been demonstrated to be effective in the treatment of oropharyngeal and/or esophageal candidiasis. The efficacy of oral solution for other indications is unknown. The two dosage forms have different absorption profiles. Itraconazole oral solution contains the excipient hydroxypropyl-b-cyclodextrin which produced adenocarcinomas of the exocrine pancreas in a rat but not in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown.

It is advisable to monitor liver function in patients receiving continuous treatment of more than 1 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 terminated. 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.

Women of Childbearing Age: In women of childbearing potential, an effective form of contraception must be used during therapy and for one 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. Itraconazole oral solution 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.

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. Such signs and symptoms include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, abdominal pain, 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).

Itraconazole binds to plasma proteins and cannot be removed by hemodialysis.

Children: The efficacy and safety of itraconazole have not been established in pediatric patients.

A pharmacokinetic study was conducted with itraconazole oral solution in 26 pediatric patients, aged 6 months to 12 years, requiring systemic antifungal treatment. Itraconazole was dosed at 5 mg/kg once daily for 2 weeks and no serious unexpected adverse events were 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: Since clinical data on the use of itraconazole oral solution in elderly patients is limited, it is advised to use itraconazole oral solution in these patients only if the potential benefit outweighs the potential risks.

Patients with Hepatic Impairment: Itraconazole is predominantly metabolized in the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. A decrease in the oral bioavailability of itraconazole from Sporanox capsules was observed in cirrhotic patients. This can also be expected with Sporanox oral solution. Therefore, it is advisable to monitor itraconazole plasma concentrations and to adapt the dose when necessary. Itraconazole treatment should not be started in patients with raised liver enzymes unless the expected benefit exceeds the risk of hepatic injury (see Warnings and Precautions, General).

Patients with Renal Insufficiency: A decrease in the oral bioavailability of itraconazole from Sporanox capsules was observed in some patients with renal insufficiency. This can also be expected with itraconazole oral solution. It is advised to monitor the itraconazole plasma concentration and to adapt the dose when necessary.

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

Acquired Immunodeficiency Syndrome (AIDS) and Neutropenic Patients: Studies with itraconazole capsules 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). However, the bioavailability of itraconazole oral solution, when tested in AIDS patients, was found satisfactory and not altered by the stage of HIV infection.

Patients on Continuous Treatment: In patients receiving continuous treatment of more than 1 month and in patients developing symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine, it is advisable to monitor liver function. If tests are abnormal, treatment should be terminated.

If neuropathy occurs that may be attributable to itraconazole oral solution, the treatment should be discontinued.

Drug Interactions:

Both itraconazole and its major metabolite, hydroxy-itraconazole, are inhibitors of the cytochrome P450 3A enzyme system. Coadministration of itraconazole and drugs primarily metabolized by the cytochrome P450 3A enzyme system may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects.

Selected Drugs That Are Predicted to Have Plasma Concentrations Increased by Itraconazolea:

Anticoagulants: warfarin

Antihistamines: terfenadineb , astemizoleb

Anti-HIV protease inhibitors: ritonavir, indinavir

Antineoplastic agents: vinca alkaloids

Benzodiazepines: midazolamb,c, triazolamb , diazepam

Calcium channel blockers: dihydropyridines

Cholesterol-lowering agents: lovastatinb , simvastatinb

Gastrointestinal motility agents: cisaprideb

Immunosuppressive agents: cyclosporine, tacrolimus

Steroids: methylprednisolone

Other: digoxin, quinidine

Anticoagulants: 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.

Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when itraconazole was coadministered with phenytoin. The physician is advised to monitor the plasma concentrations of itraconazole when phenytoin is taken concurrently, and to increase the dose of itraconazole if necessary.

Antihistamines: Coadministration of terfenadine with itraconazole has led to elevated plasma concentrations of terfenadine, resulting in rare instances of life-threatening cardiac dysrhythmia and death. Coadministration of astemizole with itraconazole has led to elevated plasma concentrations of astemizole and desmethylastemizole which may prolong the QT intervals. Therefore, concomitant administration of itraconazole with astemizole is contraindicated (see Contraindications).

Anti-HIV Protease Inhibitors: Coadministration of itraconazole with protease inhibitors primarily metabolized by the cytochrome P450 3A enzyme system, such as ritonavir or indinavir, may result in changes in plasma concentrations of both drugs. Caution is advised when these drugs are used concomitantly.

Anti-HIV Reverse Transcriptase Inhibitors: The results from a study in which 8 HIV-infected individuals were treated with zidovudine, 8±0.4 mg/kg/day, showed that the pharmacokinetics of zidovudine were not affected during concomitant administration of itraconazole capsules, 100 mg b.i.d. Other agents have not been studied.

Antimycobacterial Agents: Plasma concentrations of azole antifungal agents are reduced when given concurrently with isoniazid or rifampin. Itraconazole plasma concentrations should be monitored when itraconazole and isoniazid/rifampin are coadministered. A similar effect may be expected with rifabutin.

Antineoplastic Agents: The metabolism of vinca alkaloids may be inhibited by itraconazole. Therefore, patients receiving itraconazole concomitantly with vinca alkaloids should be monitored for an increase and/or prolongation of the effects of the latter drug product, including adverse effects such as peripheral neuropathy and ileus, and the dose of the vinca alkaloid should be adjusted appropriately.

Benzodiazepines: Coadministration of itraconazole with oral midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs. This may potentiate and prolong hypnotic and sedative effects. These agents should not be used during treatment with itraconazole. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged (see Contraindications).

Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustments may be necessary.

Cholesterol-Lowering Agents: Human pharmacokinetic data indicate that itraconazole inhibits the metabolism of lovastatin resulting in significantly elevated plasma concentrations of lovastatin or lovastatin acid, which have been associated with rhabdomyolysis. Use of HMG-CoA reductase inhibitors metabolized by the P450 3A enzyme system, such as lovastatin or simvastatin, should be temporarily discontinued during itraconazole therapy (see Contraindications).

Digoxin: Coadministration of itraconazole and digoxin has led to increased plasma concentrations of digoxin. Digoxin concentrations should be monitored at the initiation of itraconazole therapy and frequently thereafter, and the dose of digoxin should be adjusted appropriately.

Gastrointestinal Motility Agents: Human pharmacokinetic data indicate that oral ketoconazole potently inhibits the metabolism of cisapride resulting in significantly elevated plasma concentrations of cisapride. Data suggest that coadministration of oral ketoconazole and cisapride 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).

H 2 Antagonists: Reduced plasma concentrations of itraconazole were reported when itraconazole capsules were coadministered with H 2 antagonists. However, as itraconazole is already dissolved in itraconazole oral solution, the effect of H 2 antagonists is expected to be substantially less than with the capsules. Nevertheless, caution is advised when the two drugs are coadministered.

Immunosuppressive Agents: Coadministration of itraconazole and cyclosporine or tacrolimus has led to increased plasma concentrations of the latter 2 agents. Cyclosporine and tacrolimus concentrations should be monitored at the initiation of itraconazole therapy and frequently thereafter, and the dose of cyclosporine or tacrolimus should be adjusted appropriately.

Oral Hypoglycemic Agents: 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.

Quinidine: Tinnitus and decreased hearing have been reported in patients concomitantly receiving itraconazole and quinidine.

Steroids: The metabolism of methylprednisolone may be inhibited by itraconazole. Therefore, patients receiving itraconazole concomitantly with methylprednisolone should be monitored for an increase and/or prolongation of the effects of the latter drug product, including adverse effects, and the dose of methylprednisolone should be adjusted appropriately.

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

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.

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

Adverse Reactions:

Oral Solution: The adverse event profile was analyzed for 889 HIV-positive and other immunocompromised patients receiving itraconazole oral solution for the treatment of oral and esophageal candidiasis. The most frequently reported adverse events were of gastrointestinal origin. The total observed incidence of adverse events that are possibly or directly drug-related, during treatment or within 14 days post-treatment for itraconazole oral solution is 18.2%. A listing of adverse events reported with a frequency ³ 1% for itraconazole in all worldwide studies of oropharyngeal and esophageal candidiasis.

Adverse Experience Incidence ³ 1.0% in Worldwide Trials of Oropharyngeal and Esophageal Candidiasis, by Body System

Body System/Adverse Event Itraconazole n=889

Gastrointestinal System Disorder 12.3%

Nausea Diarrhea Vomiting Abdominal pain 5.3% 4.5% 3.4% 2.5%

Skin and Appendages Disorders 2.4%

Rash 1.3%

Central and Peripheral Nervous System 1.7%

Headache 1.1%

Liver and Biliary System Disorders 1.3%

Special senses 1.1%

Taste perversion 1.0%

Body as a Whole 1.0%

Capsules: Adverse experiences reported in association with the use of itraconazole capsules: the most frequently reported are of gastrointestinal 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 angioedema). Isolated cases of peripheral neuropathy and of Stevens-Johnson syndrome have also been reported: a causality for the latter was not established.

Especially in patients receiving prolonged (³ 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 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 optimal absorption, itraconazole oral solution should be taken without food. The solution should be swished in the oral cavity and swallowed. There should be no rinsing after swallowing.

Oropharyngeal Candidiasis: The recommended dosage of itraconazole oral solution for oropharyngeal candidiasis is 200 mg daily in a single dose or divided doses; treatment should continue for 1 to 2 weeks to decrease the likelihood of relapse.

Esophageal Candidiasis: The recommended dosage for esophageal candidiasis is 100 mg daily for a minimum treatment of 3 weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg/day may be used based on medical judgment of the patient’s response to therapy.

Availability And Storage:

Each mL contains: itraconazole 10 mg. Nonmedicinal ingredients: caramel flavor, cherry flavor 1 and 2, hydrochloric acid, hydroxypropyl-b-cyclodextrin, propylene glycol, purified water, sodium hydroxide, sodium saccharin and sorbitol. Amber glass bottles of 150 mL. Store at 15 to 25°C. Discard remaining unused product 3 months after opening bottle.

SPORANOX® Oral Solution Janssen-Ortho Itraconazole Antifungal

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