itraconazole (Rx)

Brand and Other Names:Sporanox, Sporanox Oral Solution, more...Onmel, Tolsura
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 65mg (Tolsura)
  • 100mg (Sporanox, generic)

oral solution

  • 10mg/mL (Sporanox, generic)

tablet

  • 200mg (Onmel)

Life-threatening Infections

Recommended loading dose based on pharmacokinetic data

Sporanox

  • Loading dose: 200 mg (2 capsules) PO TID (600 mg/day) for the first 3 days, followed by recommended dosing based on indication

Tolsura

  • Loading dose: 130 mg (2 x 65 mg capsules) PO TID (390 mg/day) for the first 3 days, followed by recommended dosing based on indication

Continue for a minimum of 3 months and until active fungal infection has subsided; an inadequate period of treatment may lead to recurrence of active infection

Blastomycosis

Indicated for treatment of blastomycosis, including pulmonary and extrapulmonary infections in immunocompromised and nonimmunocompromised adults

Sporanox

  • 200 mg PO qDay
  • If no improvement, or evidence of progressive fungal disease, increase dose in 100-mg increments to a maximum of 400 mg/day
  • Divide doses >200 mg/day into 2 doses

Tolsura

  • 130 mg PO qDay
  • If no improvement, or evidence of progressive fungal disease, increase dose in 65 mg increments to a maximum of 260 mg/day (130 mg BID)
  • Divide doses >130 mg/day into 2 doses

Aspergillosis

Indicated for treatment of pulmonary and extrapulmonary aspergillosis in immunocompromised and nonimmunocompromised adults who are intolerant of or refractory to amphotericin B therapy

Sporanox

  • 200-400 mg/day PO; may be used in combination with corticosteroids

Tolsura

  • 130 mg PO qDay or BID

Histoplasmosis

Indicated for treatment of histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis in immunocompromised and nonimmunocompromised adults

Sporanox

  • 200 mg PO qDay
  • If no improvement, or evidence of progressive fungal disease, increase dose in 100-mg increments to a maximum of 400 mg/day
  • Divide doses >200 mg/day into 2 doses

Tolsura

  • 130 mg PO qDay
  • If no improvement, or evidence of progressive fungal disease, increase dose in 65 mg increments to a maximum of 260 mg/day (130 mg BID)
  • Divide doses >130 mg/day into 2 doses

Onychomycosis

Indicated for treatment of onychomycosis of the toenail due to Trichophyton rubrum or T. mentagrophytes in nonimmunocompromised patients

Fingernails (Sporanox only): 2 treatment pulses, each consisting of 200 mg q12hr for 1 week; pulses are separated by a 3-week period without Sporanox

Toenails, with or without fingernail involvement (Sporanox, Onmel): 200 mg/day PO for 12 weeks

Candidiasis

Indicated for treatment of oropharyngeal and esophageal candidiasis

Esophageal candidiasis

  • 100 mg (10 mL) PO qDay for a minimum of 3 weeks; continue treatment for 2 weeks following resolution of symptoms
  • Doses ≤200 mg/day (20 mL) may be used based on medical judgment of the patient’s response to therapy

Oropharyngeal candidiasis

  • Oral solution only: 200 mg (20 mL) PO qDay for 1-2 weeks; signs and symptoms of oropharyngeal candidiasis generally resolve within several days
  • Unresponsive/refractory to fluconazole: 100 mg (10 mL) PO BID
  • Clinical response will be seen in 2-4 weeks
  • May be expected to relapse shortly after discontinuing therapy
  • Limited data on safety of long-term use (>6 months) of oral solution are available at this time

Otomycosis (Orphan)

Suspension: Topical treatment of fungal otitis externa (otomycosis)

Orphan indication sponsor

  • Fairfield Clinical Trials, LLC; 200 Steep Hill Road; Weston, CT 06883

Dosage Modifications

Renal impairment

  • Limited data are available on use of oral itraconazole in patients with renal impairment
  • Exercise caution when administered in this patient population

Hepatic impairment

  • Limited data are available on use of oral itraconazole in patients with hepatic impairment
  • Tolsura: In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk; monitor liver function

Dosing Considerations

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), oral bioavailability for drug may be decreased; adjust dose based on clinical response in these patients

Do not use Sporanox capsules and oral solution interchangeably; only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis

Limitations of use (Tolsura)

  • Not indicated for onychomycosis
  • NOT interchangeable or substitutable with other itraconazole products due to differences in dosing; follow specific dosage recommendations for Tolsura

Safety and efficacy not established

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Interactions

Interaction Checker

and itraconazole

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Systemic fungal infections

            • Nausea (11%)

            1-10% (Systemic fungal infections)

            Rash (9%)

            Vomiting (5%)

            Edema (4%)

            Headache (4%)

            Abnormal liver function test results (3%)

            Diarrhea (3%)

            Fever (3%)

            Fatigue (3%)

            Hypertension (3%)

            Pruritus (3%)

            Abdominal pain (2%)

            Dizziness (2%)

            Hypertriglyceridemia (2%)

            Hypokalemia (2%)

            Albuminuria (1%)

            Anorexia (1%)

            Decreased libido (1%)

            Somnolence (1%)

            Anorexia (1%)

            Impotence (1%)

            1-10% (Toenail infections)

            Headache (10%)

            Rhinitis (9%)

            Upper respiratory tract infection (8%)

            Sinusitis, injury (7%)

            Diarrhea (4%)

            Dyspepsia (4%)

            Flatulence (4%)

            Abdominal pain (4%)

            Dizziness (4%)

            Rash (4%)

            Elevated liver enzymes (4%)

            Gastrointestinal disorders (4%)

            Rash (3%)

            Cystitis (3%)

            Urinary tract infection (3%)

            Liver function abnormality (3%)

            Myalgia (3%)

            Nausea (3%)

            Hypertension (2%)

            Appetite increased (2%)

            Constipation (2%)

            Gastritis, gastroenteritis (2%)

            Pharyngitis (2%)

            Abnormal dreaming (2%)

            Orthostatic hypertension (1%)

            Headache (1%)

            Malaise (1%)

            Myalgia (1%)

            Vasculitis (1%)

            Vertigo (1%)

            Frequency Not Defined

            Hepatobiliary disorders: Hyperbilirubinemia

            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: ALT increased, AST 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: Hyperhidrosis

            Vascular disorders: Hypotension

            Postmarketing Reports

            Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia

            Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema

            Nervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia, tremor

            Eye Disorders: Visual disturbances, including vision blurred and diplopia

            Ear and labyrinth disorders: Transient or permanent hearing loss

            Respiratory, thoracic and mediastinal disorders: Pulmonary edema, dyspnea

            Gastrointestinal disorders: Pancreatitis, dysgeusia

            Hepatobiliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis

            Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria

            Musculoskeletal and connective tissue disorders: Arthralgia

            Renal and urinary disorders: Urinary incontinence, pollakiuria

            Reproductive system and breast disorders: Erectile dysfunction

            General disorders and administration site conditions: Peripheral edema

            Investigations: Blood creatine phosphokinase increased

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            Warnings

            Black Box Warnings

            Congestive heart failure

            • Can cause or exacerbate congestive heart failure (CHF)
            • When itraconazole IV was administered to healthy human volunteers and dogs, negative inotropic effects were seen
            • Do not use for the treatment of onychomycosis in patients with ventricular dysfunction (eg, history of CHF)
            • If signs or symptoms of CHF occur during administration, reassess benefit and risk of continuing treatment

            Contraindicated drug interactions

            • Itraconazole is potent CYP4503A4 inhibitor
            • Coadministration of the following drugs are contraindicated with itraconazole: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), irinotecan, ivabradine, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor
            • In patients with varying degrees of renal or hepatic impairment, coadministration of itraconazole with colchicine, fesoterodine, and solifenacin are contraindicated
            • Coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors
            • Elevated plasma concentrations of some of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs (eg, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes)

            Contraindications

            Hypersensitivity

            Contraindicated with certain CYP3A4 substrate drugs (see Black Box Warnings)

            Coadministration with colchicine, fesoterodine, and solifenacin in patients with varying degrees of renal or hepatic impairment

            Coadministration with eliglustat in patients who are poor or intermediated CYP2D6 metabolizers, or if coadministered with strong or moderate CYP2D6 inhibitors

            Increased plasma concentrations resulting from coadministration with itraconazole of some of the aforementioned drugs can lead to QT prolongation and ventricular tachyarrhythmias

            Treatment of onychomycosis in women who are pregnant or plan to become pregnant

            Cautions

            Cases of serious hepatotoxicity, including liver failure and death, reported; discontinue if liver disease develops, and perform liver function tests; readministration discouraged

            Prolongs QT interval; caution with concurrent QT-prolonging drugs or congenital long QT (see Black Box Warnings for drugs contraindicated for use with itraconazole)

            Can cause or exacerbated CHF; not for the treatment of other indications in patients with evidence of ventricular dysfunction unless benefit clearly outweighs risks; 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; monitor for signs and symptoms of CHF during treatment; if signs or symptoms of CHF appear or worsen during administration, reassess benefit-risk of continuing treatment

            Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. when co-administering itraconazole and calcium channel blockers, monitor carefully for signs and symptoms of CHF during treatment due to an increased risk of CHF

            Life-threatening cardiac arrhythmias and/or sudden death reported when coadministered with drugs that are CYP3A4 substrates and are associated with arrhythmias with increased systemic exposure (eg, pimozide, methadone, quinidine)

            Oral capsule and oral solution are not bioequivalent; do not use interchangeably

            Parenteral form is incompatible with most aqueous solutions; use dedicated line, and do not mix with other drugs in any way

            If peripheral neuropathy occurs that may be attributable to itraconazole, discontinue treatment

            If cystic fibrosis patient does not respond to itraconazole, consider switching to alternative therapy; large differences in itraconazole pharmacokinetic parameters observed in cystic fibrosis patients

            Transient or permanent hearing loss reported in patients receiving treatment with itraconazole; several reports included concurrent administration of quinidine, which is contraindicated; the hearing loss usually resolves when treatment is stopped, but can persist in some patients

            Caution with renal impairment; data are limited

            Absorption of itraconazole capsules is reduced when gastric acidity reduced; administer capsules with acidic beverage in patients with reduced gastric acidity and do not administer concomitantly with acid suppressive therapy; monitor for response

            Only oral solution shown to be effective in oral/esophageal candidiasis; oral solution not recommended in patients at immediate risk for systemic candidiasis

            Itraconazole should not be used to treat voriconazole-refractory aspergillosis; both agents may share resistance mechanisms

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            Pregnancy & Lactation

            Pregnancy

            There are no data on exposure to itraconazole during pregnancy

            Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage

            Drug should be used for treatment of systemic fungal infections in pregnancy only if benefit outweighs potential risk; therapy should not be administered for treatment of onychomycosis to pregnant patients or to women contemplating pregnancy; drug should not be administered to women of childbearing potential for treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses; highly effective contraception should be continued throughout therapy and for 2 months following the end of treatment

            Animal

            • In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (6-25 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of ~80 mg/kg/day (12 times the MRHD).

            Lactation

            Itraconazole is excreted in human milk

            No data on the amount of itraconazole in human milk, the effects on the breastfed child, or the effects on milk production

            Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for itraconazole and any potential adverse effects on the breastfed child from itraconazole or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Triazole antifungal agent; inhibits cytochrome P450-dependent synthesis of ergosterol, which in turn inhibits cell-membrane formation

            Absorption

            AUC: 15.6 hr·mcg/mL (Tolsura 130 mg BID); 14.9 hr·mcg/mL (itraconazole 200 mg BID)

            AUC (Onmel): 2.27 hr·mcg/mL (fasted); 3.34 hr·mcg/mL (fed)

            Trough plasma concentration: 1.2 mcg/mL (Tolsura 130 mg BID); 1 mcg/mL (itraconazole 200 mg BID)

            Peak plasma concentration (steady-state): 1.6 mcg/mL (Tolsura 130 mg BID); 1.5 mcg/mL (itraconazole 200 mg BID)

            Peak plasma concentration (Onmel): 162 ng/mL (fasted); 213 ng/mL (fed)

            Peak plasma time (steady-state): 7 hr (Tolsura 130 mg BID); 5 hr (itraconazole 200 mg BID)

            Peak plasma time (Onmel): 2.9 hr (fasted); 5.7 hr (fed)

            Effect of food

            • Effect of food on the steady-state pharmacokinetics of itraconazole following administration (Tolsura 130 mg BID) for 14.5 days under fed and fasted conditions was evaluated in 20 healthy volunteers
            • A high-fat meal with total caloric content of 919 calories (526 fat calories, 260 carbohydrate calories and 133 protein calories) was used in the study

            Distribution

            Protein bound: 99.8% (albumin); 0.2% (free drug)

            Metabolism

            Extensively metabolized by the liver into a large number of metabolites

            Mainly metabolized by CYP3A4

            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

            Elimination

            Half-life (fasted): 32-42 hr

            Excretion: Urine (35%); feces (54%)

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            Administration

            Oral Administration

            Do not administer with antacids

            Sporanox and generic

            • Capsule and oral solution formulations are not bioequivalent and thus are not interchangeable
            • Generally, oral solution is the preferred formulation because of improved absorption (IDSA [Kauffman 2007])
            • Capsule: Take with food
            • Solution
              • Take on an empty stomach
              • When treating oropharyngeal and esophageal candidiasis, solution should be swished vigorously in mouth (10 mL/dose), then swallowed

            Tolsura

            • Administer with food
            • Swallow whole; do not chew, crush, or break

            Storage

            Sporanox

            • Oral solution: Store ≤25°C (77°F); do not freeze
            • Capsules: Store at 25°C (77°F); excursions permitted 15-30°C (59-86°F)

            Omnel

            • Store at 25°C (77°F); excursions permitted 15-30°C (59-86°F)
            • Dispense in a tight, light resistant container

            Tolsura

            • Store at 25°C (77°F); excursions permitted 15-30°C (59-86°F)
            • Dispense in a tight, light resistant container
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            Images

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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