Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, and serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

Itraconazole capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and

onychomycosis of the fingernail due to dermatophytes (tinea unguium).

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.

CONTRAINDICATIONS:

Congestive heart failure: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

Concomitant administration of Itraconazole capsules and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine, dofetilide, and triazolam are contraindicated with Itraconazole. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with Itraconazole. 

Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

Itraconazole is contraindicated for patients who have shown hypersensitivity to Itraconazole or its excipients. There is no information regarding cross-hypersensitivity between Itraconazole and other azole antifungal agents. Caution should be used when prescribing Itraconazole to patients with hypersensitivity to other azoles.

CLINICAL PHARMACOLOGY:

Pharmacokinetics and Metabolism:

The observed absolute oral bioavailability of Itraconazole was 55%.

The oral bioavailability of Itraconazole is maximal when Itraconazole capsules are taken with a full meal. Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. The plasma protein binding of Itraconazole is 99.8% and that of hydroxyItraconazole is 99.5%. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including Hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that Itraconazole may undergo saturable metabolism with multiple dosing. 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 40% of the dose is excreted as inactive metabolites in the urine.   

Mechanism of Action: In vitro studies have demonstrated that Itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

WARNINGS:

Hepatic effects: Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Cardiac dysrhythmias: life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, or quinidine concomitantly with Itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Itraconazole is contraindicated.

Cardiac disease: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of Itraconazole therapy. If signs or symptoms of CHF appear during administration of Itraconazole capsules, discontinue administration.

PRECAUTIONS: 

General: rare cases of serious hepatotoxicity have been observed with Itraconazole treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk.

Under fasted conditions, Itraconazole absorption was decreased in the presence of decreased gastric acidity.

Pregnancy: Pregnancy Category C

Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of Itraconazole therapy for the mother should be weighed against the potential risk from exposure of Itraconazole to the infant.

Pediatric Use: the efficacy and safety of Itraconazole have not been established in pediatric patients.

HIV-Infected Patients: because hypochlorhydria has been reported in HIV-infected individuals, the absorption of Itraconazole in these patients may be decreased.

Drug Interactions:

Antiarrhythmics: digoxin, dofetilide, quinidine

Anticonvulsants: carbamazepine, phenobarbital, phenytoin

Antimycobacterials: rifampin, isoniazid, rifabutin.

Antineoplastics: busulfan, docetaxel, vinca alkaloids

Antipsychotics: pimozide

Benzodiazepines: alprazolam, diazepam, midazolam, triazolam

Calcium channel blockers: dihydropyridines, verapamil

Gastrointestinal motility agents: cisapride

HMG CoA-reductase inhibitors: atorvastatin, cerivastatin, lovastatin,

Immunosuppressants cyclosporine: tacrolimus, sirolimus

Oral hypoglycemics: oral hypoglycemics

Protease inhibitors: indinavir, ritonavir, saquinavir

Other alfentanil, buspirone, methylprednisolone, trimetrexate, warfarin

Gastric acid  suppressors/neutralizers  antacids: H 2 -receptor antagonists, proton pump inhibitors

Non-nucleoside reverse transcriptase inhibitors: nevirapine

Macrolide antibiotics: clarithromycin, erythromycin

SIDE EFFECTS:

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Adverse events occurring with an incidence of greater than or equal to 1%

Gastrointestinal: Nausea, Vomiting, Diarrhea, Abdominal Pain, Anorexia,

Body as a whole: Edema, Fatigue, Fever, Malaise,

Skin and Appendages: Rash, Pruritus

Central/Peripheral nrvous sstem: Headache , Dizziness ,Psychiatric, Libido Decreased Somnolence, 

Cardiovascular: Hypertension

Metabolic/Nutritional: Hypokalemia

Urinary System: Albuminuria

Liver and Biliary system: Hepatic function abnormal

Reproductive system, male: Impotence

Adverse event incidence (%)

Elevated liver enzymes (greater than twice the upper limit of normal) 4, Gastrointestinal disorders 4, Rash 3, Hypertension 2, Orthostatic Hypotension 1, Headache 1, Malaise 1, Myalgia 1, Vasculitis 1,Vertigo 1

OVERDOSAGE:

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of Itraconazole. In patients taking either 3000 mg of Itraconazole Capsules, the adverse event profile was similar to that observed at recommended doses.

DOSAGE AND ADMINISTRATION:

Treatment of blastomycosis and histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). 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 two divided doses.

Treatment of aspergillosis: a daily dose of 200 to 400 mg is recommended.

Treatment in life-threatening situations: in life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously, although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.

Treatment should be continued for a minimum of three 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.

Treatment of onychomycosis: toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of onychomycosis: fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without Itraconazole.  

How Supplied: Each pack of Ruz-Itraconazole 100 mg contains 20 capsules in 2 blisters.

Storage: Store at controlled room temperature below 30°C. Protect from light and moisture.

For more information please refer to:

                  PDR 2000, page 1457-60

                  USPDI for Professional Health Care, 2004, Page 314-22

                  Martindale 2005, Page 402-3