itraconazole (Capsule)

itraconazole (Capsule)

Itraconazole is a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: (��)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-one mixture with (��)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-one or (��)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-��-1,2,4-triazolin-5-one. Itraconazole has a molecular formula of CHClNOand a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols and freely soluble in dichloromethane. It has a pKa of 3.7 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. Each capsule, for oral administration, contains 100 mg of itraconazole. In addition, each capsule contains the following inactive ingredients: corn starch, hypromellose, polyethylene glycol (PEG) 20,000 and sugar spheres. The capsule shell contains: D&C yellow #10 aluminum lake, FD&C blue #1, FD&C blue #2, FD&C red #40, gelatin, iron oxide black, pharmaceutical glaze, propylene glycol and titanium dioxide.

dailymed-ingredient:itraconazole

Itraconazole capsules are available containing 100 mg of itraconazole, with an aqua blue opaque cap, light blue clear body, imprinted���550���in black ink on cap and body, filled with white to off-white pellets. Itraconazole capsules are supplied in bottles of 28, 30, 100 and 500 capsules and in a 7-Day Treatment Pack (cartons containing 7 blister packs of 4 capsules each). Store at 20��to 25��C (68��to 77��F) [see USP Controlled Room Temperature]. Protect from light and moisture.

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. If signs or symptoms of congestive heart failure occur during administration of itraconazole capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide or levacetylmethadol (levomethadyl) with itraconazole capsules, injection or oral solution is contraindicated. Itraconazole, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl) or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS; WARNINGS and PRECAUTIONS, Drug Interactions for more information.

dailymed-ingredient:D&C_yellow_#10_aluminum_lake, dailymed-ingredient:FD&C_blue_#1, dailymed-ingredient:FD&C_blue_#2, dailymed-ingredient:FD&C_red_#40, dailymed-ingredient:corn_starch, dailymed-ingredient:gelatin, dailymed-ingredient:hypromellose, dailymed-ingredient:iron_oxide_black, dailymed-ingredient:pharmaceutical_glaze, dailymed-ingredient:polyethylene_glycol_(PEG)_20,000, dailymed-ingredient:propylene_glycol, dailymed-ingredient:sugar_spheres, dailymed-ingredient:titanium_dioxide

Ge neral: 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. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to itraconazole capsules, the treatment should be discontinued. Itraconazole capsules should be administered after a full meal. Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated . The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Patients should be informed of this potential side effect and advised to discontinue therapy and inform their physiciansif any hearing loss symptoms occur.<br/>Information for Patients:<br/>Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazolea below and the following drug class subheadings that follow):<br/>Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.<br/>Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine.<br/>Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of itraconazole could be substantially reduced if given concomitantly with one of these agents. Co-administration is not recommended.<br/>Antineoplastics: Itraconazole may inhibit the metabolism of busulfan, docetaxel and vinca alkaloids.<br/>Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of pimozide with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and pimozide is contraindicated.<br/>Benzodiazepines: Concomitant administration of itraconazole and alprazolam, diazepam, oral midazolam or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of itraconazole and oral midazolam or triazolam is contraindicated. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.<br/>Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and nisoldipine is contraindicated.<br/>Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when itraconazole capsules were administered concomitantly with H-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, itraconazole should be administered with a cola beverage if the patient has achlorhydria or is taking H-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of itraconazole capsules. In a clinical study, when itraconazole capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced.<br/>Gastrointestinal Motility Agents: Co-administration of itraconazole with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole with cisapride is contraindicated.<br/>HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of itraconazole with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated.<br/>Immunosuppressants: Concomitant administration of itraconazole and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of itraconazole and sirolimus could increase plasma concentrations of sirolimus.<br/>Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazolea ) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cand AUC���of itraconazole increased by 44% (90% CI: 119% to 175%) and 36% (90% CI: 108% to 171%), respectively.<br/>Non-Nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with itraconazole capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8��0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.<br/>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 co-administered.<br/>Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.<br/>Protease Inhibitors: Concomitant administration of itraconazole and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of itraconazole and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when itraconazole and protease inhibitors must be given concomitantly.<br/>Other:<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10 x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1 x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25 x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T��C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5 x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20 x MRHD).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>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. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.<br/>Pediatric Use: The efficacy and safety of itraconazole have not been established in pediatric patients. No pharmacokinetic data on itraconazole capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpectedadverse events have been reported. Itraconazole oral solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones and increased bone fragility. At a dosage level of 80 mg/kg/day (10 x MRHD) over 1 year or 160 mg/kg/day (20 x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.<br/>HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.<br/>Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.<br/>Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population.

itraconazole

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. The risks and benefits of itraconazole use should be reassessed.<br/>Adverse Events in the Treatment of Systemic Fungal Infections: Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia and male breast pain.<br/>Adverse Events Reported in Toenail Onychomycosis Clinical Trials: Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache 10%, rhinitis 9%, upper respiratory tract infection 8%, sinusitis, injury 7%, diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash 4%, cystitis, urinary tract infection, liver function abnormality, myalgia, nausea 3%, appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming 2%.<br/>Adverse Events Reported in Fingernail Onychomycosis Clinical Trials: Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache 8%, pruritus, nausea, rhinitis 5%, rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury 3%.<br/>Post-Marketing Experience: Worldwide post-marketing experiences with the use of itraconazole include very rare reports (<1/10,000) of the adverse events listed below: There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with itraconazole has not been established.

Itraconazole capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, 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: 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.<br/>Description of Clinical Studies:<br/>Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis, compared with the natural history of untreated cases.<br/>Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole, for the treatment of histoplasmosis, compared with the natural history of untreated cases.<br/>Histoplasmosis in HIV-Infected Patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.<br/>Aspergillosis: Analyses were conducted on data from an open-label,���single-patient-use���protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 mg to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.<br/>Onychomycosis of the Toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).<br/>Onychomycosis of the Fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week pulse of 200 mg of itraconazolecapsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.

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