Itraconazole Capsule   is the generic name for itraconazole, an azole  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]-Δ2-1,2,4-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]-Δ2-1,2,4-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]-Δ2-1,2,4-triazolin-5-one

Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white or almost white powder. It is freely soluble in methylene chloride, sparingly soluble in tetrahydrofuran, very slightly soluble in alcohol and practically insoluble in water. 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.

Itraconazole capsules contain 100 mg of itraconazole coated on sugar spheres (composed of  sucrose, starch and purified water). Inactive ingredients are hydroxypropyl methylcellulose, polyethylene glycol, gelatin, titanium dioxide, D&C Red No. 22, FD&C Blue No. 1, and D&C Red No. 28.

The imprinting ink contains shellac, propylene glycol, black iron oxide, and potassium hydroxide.

Pharmacokinetics and Metabolism:

General Pharmacokinetic Characteristics

Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%.

The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See PRECAUTIONS: Drug Interactions.) Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone. (See PRECAUTIONS: Drug Interactions.)

Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the same dose of drug is given. (See WARNINGS)

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.

Metabolism

Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.

Excretion

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.

As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.

Special Populations:

Renal Impairment:

Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50 to 79 mL/min), moderate (defined in this study as CrCl 20 to 49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min) were similar to that in healthy subjects (range of means 42 to 49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Hepatic Impairment:

Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37±17 hours vs. 16±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.)

Decreased Cardiac Contractility:

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of itraconazole capsules, itraconazole should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)

MICROBIOLOGY

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.

Antimicrobial Activity:

Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species (See INDICATIONS AND USAGE: Description of Clinical Studies).

Susceptibility Testing Methods:

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Resistance:

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.

Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

Cross-resistance:

Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.

Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.

Itraconazole capsules   are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:

            1. Blastomycosis, pulmonary and extrapulmonary

            2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non- meningeal histoplasmosis, and

            3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

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:

            1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and

            2. 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.

(See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Description of Clinical Studies:

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.

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.

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.

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 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.

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).

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 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 course of 200 mg of itraconazole capsules   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.

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. (See BOXED WARNINGS, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.)

Drug Interactions:

Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole. Plasma concentrations increase for the following drugs:  methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride,naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in PRECAUTIONS: Drug Interactions.

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

Itraconazole are contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited 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.

Hepatic Effects:

Itraconazole have 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, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued itraconazole use or reinstitution of treatment with itraconazole   is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)

Cardiac Dysrhythmias:

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

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. Itraconazole capsules   should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. 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 felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Interaction potential:  

Itraconazole has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability:  

Itraconazole capsules and itraconazole Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.)

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.

Table 3: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1%

* Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive  medications.

Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.

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.

Table 4: Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading 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%.

 Adverse Events Reported in Fingernail Onychomycosis Clinical Trials

Patients in these trials were on a dosing 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.

Table 5: Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading 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%.  

Adverse Events Reported from Other Clinical Trials  

 In addition, the following adverse drug reaction was reported in patients who participated in itraconazole capsules clinical trials: Hepatobiliary Disorders: hyperbilirubinemia. 

 The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole Oral Solution and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration:  

Cardiac Disorders: cardiac failure, left ventricular failure, tachycardia;  

General Disorders and Administration Site Conditions: face edema, chest pain, chills;  

Hepatobiliary Disorders: hepatic failure, jaundice; 

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal;  

Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia;  

Psychiatric Disorders: confusional state; 
Renal and Urinary Disorders: renal impairment; 

Respiratory, Thoracic and Mediastinal Disorders: dysphonia, cough;  

Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis; 

Vascular Disorders: hypotension
 

Post-marketing Experience

Adverse drug reactions that have been first identified during  post-marketing experience with itraconazole(all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 6: Postmarketing Reports of Adverse Drug Reactions

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.  See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures should be employed. Contact a certified poison control center for the most up to date information on the management of itraconazole capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole. (See ADVERSE REACTIONS.)

Itraconazole capsulesshould be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole.

Itraconazole capsule   is a different preparation than itraconazole   Oral Solution and should not be used interchangeably.

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.

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.

Itraconazole capsules   and itraconazole Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

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 two 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.

Use in Patients with 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. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .)

Use in Patients with 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. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)

Itraconazole capsules are supplied as follows:
100 mg:

Blue opaque cap/pink transparent body size “0” hard gelatin capsules having imprinting “A” on cap with black ink and “175” on body with black ink filled with white to off-white pellets. 

NDC 62332-204-30        Bottle of    30 Capsules
NDC 62332-204-90        Bottle of    90 Capsules
NDC 62332-204-71        Bottle of    500 Capsules
NDC 62332-204-10        Unit Dose Capsules of  100 (Blisters of 10)
NDC 62332-204-04        7 Blister Packs x 4 Capsules Each (7 Day Treatment Pack)

Store at controlled room temperature 15° to 25°C (59° to 77°F). Protect from light and moisture.
Keep out of reach of children.
Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797.

Manufactured by:
Alembic Pharmaceuticals Limited
(Formulation Division),
Panelav 389350, Gujarat, India

Manufactured for:
Alembic Pharmaceuticals, Inc.
750 Route 202, Bridgewater, NJ 08807
USA

Revised: 11/2019

Itraconazole (IT-ra-KON-a-zole) Capsules 

Rx Only

Read this Patient Information that comes with itraconazole capsules before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about itraconazole capsules? Itraconazole capsules can cause serious side effects, including:

1. Heart failure. Do not take itraconazole capsules if you have had heart failure, including congestive heart failure.

Stop taking itraconazole capsules and call your healthcare provider right away if you have any of these symptoms of congestive heart failure:

 
2. Heart problems and other serious medical problems. Serious medical problems that affect the heart and other parts of your body can happen if you take itraconazole capsules with certain other medicines. Do not take itraconazole capsules if you also take the following medicines:

This is not a complete list of medicines that can interact with itraconazole capsules. Itraconazole capsules may affect the way other medicines work, and other medicines may affect how itraconazole capsules works. You can ask your pharmacist for a list of medicines that interact with itraconazole capsules.

Before you start taking itraconazole capsules, tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start any new medicine, ask your healthcare provider or pharmacist if it is safe to take it with itraconazole capsules.

3. Liver problems. Itraconazole capsules can cause serious liver problems which may be severe and lead to death. Stop taking itraconazole capsules and call your healthcare provider right away if you have any of these symptoms of liver problems:

For more information about side effects, see “What are the possible side effects of itraconazole capsules?”

What is itraconazole capsule?

• Itraconazole capsule is a prescription medicine used to treat the following fungal infections of the toenails, fingernails and other parts of the body: blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
• It is not known if itraconazole capsule is safe and effective in children.

Do not take itraconazole capsule if you:

• have or have had heart failure, including congestive heart failure.
• take certain medicines. See “What is the most important information I should know about itraconazole capsules?”
• are pregnant or plan to become pregnant. Itraconazole capsules can harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking itraconazole capsules. Females who are able to become pregnant must use effective forms of birth control during treatment and for 2 months after stopping treatment with itraconazole capsules.
• are allergic to itraconazole or any of the ingredients in itraconazole capsules. See the end of this Patient Information leaflet for a complete list of ingredients in itraconazole capsules.

Before taking itraconazole capsules, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems.
• have liver problems.
• have kidney problems.
• have a weakened immune system (immunocompromised).
• have lung problems including cystic fibrosis.
• are breastfeeding or plan to breastfeed. Itraconazole can pass into your breast milk. You and your healthcare provider should decide if you will take itraconazole capsules or breastfeed.

Taking itraconazole capsules with certain medicines may affect each other. Taking itraconazole capsules with other medicines can cause serious side effects.

How should I take itraconazole capsules?

• Take itraconazole capsules exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much itraconazole capsules to take and when to take it.
• You will receive itraconazole capsules in a blister pack, bottle or 7 Day Treatment Pack. Your healthcare provider will decide the type of itraconazole capsules that is right for you.
• Take itraconazole capsules with a full meal.
• Swallow itraconazole capsules whole.
• You should not take itraconazole oral solution instead of itraconazole capsules, because they will not work the same way.
• If you take too much itraconazole capsules, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking itraconazole capsules?

Itraconazole capsules can cause dizziness and vision problems. Do not drive or operate machinery until you know how itraconazole capsule affects you.

What are the possible side effects of itraconazole capsules?

Itraconazole capsules may cause serious side effects, including:

• See “What is the most important information I should know about itraconazole capsules?”
• Nerve problems (neuropathy). Call your healthcare provider right away if you have tingling or numbness in your hands or feet. Your healthcare provider may stop your treatment with itraconazole capsules if you have nerve problems.
• Hearing loss. Hearing loss can happen for a short time or permanently in some people who take itraconazole capsules. Stop taking itraconazole capsules and call your healthcare provider right away if you have any changes in your hearing.

The most common side effects of itraconazole capsules include: headache, rash, and digestive system problems (such as nausea and vomiting). Additional possible side effects include upset stomach, vomiting, constipation, fever, inflammation of the pancreas, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or hair loss.

These are not all the possible side effects of itraconazole capsules.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store itraconazole capsules?

• Store itraconazole capsules at room temperature between 15° to 25°C (59° to 77°F).
• Keep itraconazole capsules dry and away from light.

Keep itraconazole capsules and all medicines out of the reach of children.

General information about the safe and effective use of itraconazole capsules.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use itraconazole capsules for a condition for which it was not prescribed. Do not give itraconazole capsules to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your doctor or pharmacist for information about itraconazole capsules that is written for health professionals.

What are the ingredients in itraconazole capsules?

Active ingredients: itraconazole (coated on sugar spheres composed of sucrose, starch and purified water)

Inactive ingredients: hydroxypropyl methylcellulose, polyethylene glycol, gelatin, titanium dioxide, D&C Red No. 22, FD&C Blue No. 1, and D&C Red No. 28. The imprinting ink contains shellac, propylene glycol, black iron oxide, and potassium hydroxide.

This patient information has been approved by the U.S. Food and Drug Administration.

Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

USA

Revised: 11/2019

NDC 62332-204-30
Itraconazole 
Capsules
100 mg
Rx only
30 Capsules
Alembic

NDC 62332-204-04
Itraconazole Capsules
100 mg
7 Day Treatment Pack
•7  days of treatment
•Product information
28 Capsules
(Contains 7  blisters x 4 capsules each) 
Rx only
Alembic