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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Itraconazole may be confused with fluconazole
Sporanox® may be confused with Suprax®, Topamax®
Pronunciation
(i tra KOE na zole)
U.S. Brand Names
Generic Available
Yes: Capsule
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral capsules: Treatment of susceptible fungal infections in immunocompromised and immunocompetent patients including blastomycosis and histoplasmosis; indicated for aspergillosis (in patients intolerant/refractory to amphotericin B), and onychomycosis of the toenail and fingernail (in nonimmunocompromised patients)
Oral solution: Treatment of oral and esophageal candidiasis
Use: Dental
Treatment of susceptible fungal infections in immunocompromised and immunocompetent patients including blastomycosis and histoplasmosis; has activity against Aspergillus, Candida, Coccidioides, Cryptococcus, Sporothrix, and chromomycosis. Useful in superficial mycoses including dermatophytoses (eg, tinea capitis), pityriasis versicolor, sebopsoriasis, vaginal and chronic mucocutaneous candidiases; systemic mycoses including candidiasis, meningeal and disseminated cryptococcal infections, paracoccidioidomycosis, coccidioidomycoses; miscellaneous mycoses such as sporotrichosis, chromomycosis, leishmaniasis, fungal keratitis, alternariosis, zygomycosis.
Pregnancy Risk Factor
C
Pregnancy Considerations
Should not be used to treat onychomycosis during pregnancy. Effective contraception should be used during treatment and for 2 months following treatment. Congenital abnormalities have been reported during postmarketing surveillance, but a causal relationship has not been established.
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to itraconazole (use caution in patients with a history of hypersensitivity to other azoles), any component of the formulation; concurrent administration with cisapride, dofetilide, ergot derivatives, levomethadyl, lovastatin, midazolam (oral), nisoldipine, pimozide, quinidine, simvastatin, or triazolam; treatment of onychomycosis (or other non-life-threatening indications) in patients with evidence of ventricular dysfunction, heart failure (HF) or a history of HF; treatment of onychomycosis in patients who are pregnant or intend on becoming pregnant
Warnings/Precautions
Boxed warnings:
• Heart failure: See “Concerns related to adverse effects”
• High potential for interactions: See “Concurrent drug therapy issues” below.
• Onychomycosis: See “Disease-related concerns” below.
Concerns related to adverse effects:
• Hearing loss: Transient or permanent hearing loss has been reported. Quinidine (a contraindicated drug) was used concurrently in several of these cases. Hearing loss usually resolves after discontinuation, but may persist in some patients.
• Heart failure (HF): [U.S. Boxed Warning]: Negative inotropic effects have been observed following intravenous administration. Discontinue or reassess use if signs or symptoms of HF occur during treatment. CHF has been reported, particularly in patients receiving a total daily oral dose of 400 mg. Use with caution in patients with risk factors for HF (COPD, renal failure, edematous disorders, ischemic or valvular disease).
• Hepatotoxicity: Rare cases of serious hepatotoxicity (including liver failure and death) have been reported (including some cases occurring within the first week of therapy); hepatotoxicity was reported in some patients without pre-existing liver disease or risk factors. Use with caution in patients with pre-existing hepatic impairment; monitor liver function closely and dosage adjustment may be warranted. Not recommended for use in patients with active liver disease, elevated liver enzymes, or prior hepatotoxic reactions to other drugs unless the expected benefit exceeds the risk of hepatotoxicity.
• Neuropathy: Discontinue if signs or symptoms of neuropathy occurs during treatment.
Disease-related concerns:
• Cystic fibrosis: Large differences in itraconazole pharmacokinetic parameters have been observed in cystic fibrosis patients receiving the solution; if a patient with cystic fibrosis does not respond to therapy, alternate therapies should be considered.
• Onychomycosis: [U.S. Boxed Warning]: Not recommended for treatment of onychomycosis in patients with ventricular dysfunction or a history of HF.
• Renal impairment: Use with caution in patients with renal impairment; limited information is available.
Concurrent drug therapy issues:
• Calcium channel blockers (CCBs): May cause additive negative inotropic effects when used concurrently with itraconazole. Itraconazole may also inhibit the metabolism of CCBs. Therefore, use caution with concurrent use of itraconazole and CCBs due to an increased risk of heart failure. Concurrent use of itraconazole and nisoldipine is contraindicated.
• High potential for interactions: [U.S. Boxed Warning]: Serious cardiovascular adverse events including, QT prolongation, ventricular tachycardia, torsade de pointes, cardiac arrest and/or sudden death have been observed due to increased cisapride, pimozide, quinidine, dofetilide or levomethadyl concentrations induced by itraconazole; concurrent use contraindicated. Additionally, the following drugs metabolized by the CYP 3A4 isoenzyme system are also contraindicated: Ergot derivatives, lovastatin, midazolam (oral), simvastatin, and triazolam.
Dosage form specific issues:
• Oral/esophageal candidiasis: Only the oral solution has proven efficacy; mucosal exposure may vary between the oral solution and capsules
• Oral solution: Initiation of treatment with oral solution is not recommended in patients at immediate risk for systemic candidiasis (eg, patients with severe neutropenia).
• Product interchangeability: Due to differences in bioavailability, oral capsules and oral solution cannot be used interchangeably.
Adverse Reactions
>10%: Gastrointestinal: Nausea (11%), diarrhea (3% to 11%)
1% to 10%:
Cardiovascular: Edema (4%), hypertension (3%), chest pain (3%)
Central nervous system: Fever (3% to 7%), headache (4%), fatigue (2% to 3%), dizziness (2%), depression (2%)
Dermatologic: Rash (4% to 9%), pruritus (3%)
Endocrine & metabolic: Hypokalemia (2%)
Gastrointestinal: Vomiting (5% to 7%), abdominal pain (2% to 6%), constipation (2%)
Hepatic: LFTs abnormal (3%)
Respiratory: Rhinitis (5% to 9%), cough (4%), dyspnea (2%), pneumonia (2%), sinusitis (2%), sputum increased (2%)
Miscellaneous: Diaphoresis increased (3%)
<2%, postmarketing, and/or case reports: Adrenal insufficiency, albuminuria, allergic reactions, alopecia, anaphylactoid reactions, anaphylaxis, angioedema, anorexia, arrhythmia, arthralgia, asthenia, blurred vision, diplopia, dysgeusia, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, flatulence, gastritis, gynecomastia, hearing loss, heart failure, hematuria, hepatic failure, hepatitis, hepatotoxicity, hepatitis, hot flashes, hypertriglyceridemia, hypoesthesia, impotence, insomnia, leukocytoclastic dermatitis, leukopenia, libido decreased, malaise, menstrual disorders, myalgia, neutropenia, paresthesia, peripheral neuropathy, photosensitivity, pollakiuria, pulmonary edema, pharyngitis, rigors, serum sickness, somnolence, Stevens-Johnson syndrome, stomatitis ulcerative, thrombocytopenia, taste perversion, tinnitus, toxic epidermal necrolysis, urinary incontinence, urticaria, vasculitis
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP3A4 (strong)
Drug Interactions
Alfentanil: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Alfentanil. Risk D: Consider therapy modification
Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Risk X: Avoid combination
Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Risk D: Consider therapy modification
Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk C: Monitor therapy
Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapy
Antacids: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Aprepitant: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Aprepitant. Risk C: Monitor therapy
Benzodiazepines (metabolized by oxidation): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Exceptions: Quazepam. Risk D: Consider therapy modification
Bosentan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Bosentan. Risk C: Monitor therapy
Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Risk C: Monitor therapy
BusPIRone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of BusPIRone. Risk D: Consider therapy modification
Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Busulfan. Risk C: Monitor therapy
Calcium Channel Blockers: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Exceptions: Clevidipine. Risk D: Consider therapy modification
CarBAMazepine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Cardiac Glycosides: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification
Ciclesonide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ciclesonide. Specifically, concentrations of the active des-ciclesonide metabolite may be increased. Risk C: Monitor therapy
Cilostazol: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Cilostazol. Risk D: Consider therapy modification
Cisapride: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cisapride. Risk X: Avoid combination
Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Risk X: Avoid combination
Corticosteroids (Orally Inhaled): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Corticosteroids (Orally Inhaled). Exceptions: Beclomethasone; Beclomethasone, Systemic; Flunisolide; Flunisolide, Systemic; Triamcinolone; Triamcinolone, Systemic. Risk C: Monitor therapy
Corticosteroids (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE, Systemic: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE, Systemic. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dabigatran Etexilate: P-Glycoprotein Inhibitors may increase the serum concentration of Dabigatran Etexilate. Risk X: Avoid combination
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Risk D: Consider therapy modification
Docetaxel: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Docetaxel. Risk D: Consider therapy modification
Dofetilide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Dofetilide. Risk X: Avoid combination
Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Risk X: Avoid combination
Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Risk C: Monitor therapy
Efavirenz: May decrease the serum concentration of Itraconazole. Risk D: Consider therapy modification
Eletriptan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Eletriptan. Risk D: Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Risk X: Avoid combination
Eplerenone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Eplerenone. Risk D: Consider therapy modification
Ergot Derivatives: Itraconazole may increase the serum concentration of Ergot Derivatives. Risk X: Avoid combination
Erlotinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Erlotinib. Risk C: Monitor therapy
Eszopiclone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Eszopiclone. Risk C: Monitor therapy
Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Risk X: Avoid combination
FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Risk D: Consider therapy modification
Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Fexofenadine: Itraconazole may increase the serum concentration of Fexofenadine. Risk C: Monitor therapy
Fosaprepitant: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosaprepitant. Specifically, concentrations of aprepitant are likely to be increased. Risk C: Monitor therapy
Gefitinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Gefitinib. Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This specifically applies to oral antifungal administration, and the interaction may be different depending on specific dosage form being used. Risk C: Monitor therapy
GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Risk C: Monitor therapy
H2-Antagonists: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Risk X: Avoid combination
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HMG-CoA Reductase Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Fluvastatin; Pitavastatin; Rosuvastatin. Risk D: Consider therapy modification
Imatinib: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Imatinib. Risk C: Monitor therapy
Irinotecan: Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Irinotecan. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Risk D: Consider therapy modification
Losartan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Losartan. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Macrolide Antibiotics. Exceptions: Azithromycin; Azithromycin, Systemic; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification
Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: When used with a strong CYP3A4 inhibitor, the adult dose of maraviroc should be decreased to 150 mg twice daily. Risk D: Consider therapy modification
Methadone: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Methadone. Risk C: Monitor therapy
Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination
Paliperidone: Itraconazole may decrease the metabolism of Paliperidone. Risk C: Monitor therapy
Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Risk C: Monitor therapy
Pazopanib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pazopanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required. Risk D: Consider therapy modification
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Phosphodiesterase 5 Inhibitors. Risk D: Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Pimozide. Risk X: Avoid combination
Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: Monitor therapy
Protease Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Limit indinavir adult dose to 600 mg every 8 hours with itraconazole or ketoconazole. With ritonavir, limit ketoconazole adult dose to 200 mg/day. Limit fluconazole, itraconazole, and ketoconazole to 200 mg (adult dose) with tipranavir/ritonavir. Risk D: Consider therapy modification
Proton Pump Inhibitors: May decrease the serum concentration of Itraconazole. Risk D: Consider therapy modification
QuiNIDine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of QuiNIDine. Management: Itraconazole, voriconazole, and posaconazole are specifically contraindicated with quinidine. Use of quinidine with any azole antifungal may require quinidine dose adjustment and should be done with caution and close monitoring. Risk X: Avoid combination
Ramelteon: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ramelteon. Risk C: Monitor therapy
Ranolazine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ranolazine. Risk X: Avoid combination
Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Risk X: Avoid combination
Repaglinide: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Repaglinide. Management: Concurrent use of an azole antifungal with both repaglinide and gemfibrozil should be avoided. Risk C: Monitor therapy
Rifamycin Derivatives: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Rifamycin Derivatives. Only rifabutin appears to be affected. Rifamycin Derivatives may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Risk X: Avoid combination
Romidepsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Romidepsin. Risk X: Avoid combination
Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Risk X: Avoid combination
Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Limit saxagliptin adult dose to 2.5 mg/day and monitor for increased saxagliptin levels/effects (e.g., hypoglycemia) when used with a strong CYP3A4 inhibitor. Monitor for decreased saxagliptin levels/effects if discontinuing CYP3A4 inhibitor. Risk D: Consider therapy modification
Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Risk X: Avoid combination
Sirolimus: Itraconazole may increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Solifenacin: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Solifenacin. Risk D: Consider therapy modification
Sorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib. Risk C: Monitor therapy
Sucralfate: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Risk C: Monitor therapy
Sunitinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Sunitinib. Risk D: Consider therapy modification
Tacrolimus: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification
Tacrolimus, Systemic: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus, Systemic. Risk D: Consider therapy modification
Tacrolimus, Topical: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus, Topical. Risk C: Monitor therapy
Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Erectile dysfunction: tadalafil max = 2.5 mg/day (daily use) or 10 mg/72 hrs (as needed use) (adult doses). Avoid use of tadalafil with a strong CYP3A4 inhibitor for treatment of pulmonary arterial hypertension. Risk D: Consider therapy modification
Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk X: Avoid combination
Temsirolimus: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are likely to be increased more substantially than those of the parent temsirolimus. Risk D: Consider therapy modification
Tolterodine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk D: Consider therapy modification
Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Trimetrexate: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Trimetrexate. Risk C: Monitor therapy
VinBLAStine: Itraconazole may increase the serum concentration of VinBLAStine. Risk C: Monitor therapy
VinCRIStine: Itraconazole may enhance the adverse/toxic effect of VinCRIStine. Itraconazole may increase the serum concentration of VinCRIStine. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Itraconazole may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Ziprasidone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ziprasidone. Risk C: Monitor therapy
Zolpidem: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Zolpidem. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Food:
Capsules: Absorption enhanced by food and possibly by gastric acidity. Cola drinks have been shown to increase the absorption of the capsules in patients with achlorhydria or those taking H2-receptor antagonists or other gastric acid suppressors. Avoid grapefruit juice.
Solution: Food decreases the bioavailability and increases the time to peak concentration.
Herb/Nutraceutical: St John's wort may decrease itraconazole levels.
Storage
Capsule: Store at room temperature, 15°C to 25°C (59°F to 77°F). Protect from light and moisture.
Oral solution: Store at ?25°C (77°F); do not freeze.
Mechanism of Action
Interferes with cytochrome P450 activity, decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting cell membrane formation
Pharmacodynamics/Kinetics
Absorption: Requires gastric acidity; capsule better absorbed with food, solution better absorbed on empty stomach
Distribution: Vd (average): 796 ± 185 L or 10 L/kg; highly lipophilic and tissue concentrations are higher than plasma concentrations. The highest concentrations: adipose, omentum, endometrium, cervical and vaginal mucus, and skin/nails. Aqueous fluids (eg, CSF and urine) contain negligible amounts.
Protein binding, plasma: 99.8%; metabolite hydroxy-itraconazole: 99.5%
Metabolism: Extensively hepatic via CYP3A4 into >30 metabolites including hydroxy-itraconazole (major metabolite); appears to have in vitro antifungal activity. Main metabolic pathway is oxidation; may undergo saturation metabolism with multiple dosing.
Bioavailability: Variable, ~55% (oral solution) in 1 small study; Note: Oral solution has a higher degree of bioavailability (149% ± 68%) relative to oral capsules; should not be interchanged
Half-life elimination: Oral: Single dose: ~21 hours, steady state: 64 hours; Cirrhosis (single dose): 37 hours (range 20-54 hours)
Time to peak, plasma: Capsules: 3-5 hours; Oral solution: 2-3 hours
Excretion: Urine (<0.03% active drug, 40% as inactive metabolites); feces (~3% to 18%)
Dosage
Oral:
Usual dosage ranges:
Children: Efficacy and safety have not been established; a small number of patients 3-16 years of age have been treated with 100 mg/day for systemic fungal infections with no serious adverse effects reported. A dose of 5 mg/kg once daily was used in a pharmacokinetic study using the oral solution in patients 6 months to 12 years; duration of study was 2 weeks.
Adults: 100-400 mg/day; doses >200 mg/day are given in 2 divided doses; length of therapy varies from 1 day to >6 months depending on the condition and mycological response
Indication-specific dosing:
Adults:
Aspergillosis, invasive (salvage therapy): Duration of therapy should be a minimum of 6-12 weeks or throughout period of immunosuppression: Oral: 200-400 mg/day; Note: 2008 IDSA guidelines recommend 600 mg/day for 3 days, followed by 400 mg/day
Appropriate use: Itraconazole should NOT be used for voriconazole-refractory aspergillosis since the same antifungal and/or resistance mechanism(s) may be shared by both agents. Itraconazole oral solution and capsule formulations are not bioequivalent or interchangeable. Due to variable bioavailability of oral preparations, therapeutic drug monitoring advisable.
Aspergillosis, allergic (ABPA, sinusitis): 200 mg/day; may be used in conjunction with corticosteroids
Blastomycosis: 200 mg 3 times/day for 3 days, then 200 mg twice daily for 6-12 months; in moderately-severe to severe infection, therapy should be initiated with ~2 weeks of amphotericin B (Chapman, 2008)
Brain abscess: Cerebral phaeohyphomycosis (dematiaceous): 200 mg twice daily for at least 6 months with amphotericin
Candidiasis:
Oropharyngeal: Oral solution: 200 mg once daily for 1-2 weeks; in patients unresponsive or refractory to fluconazole: 100 mg twice daily (clinical response expected in 1-2 weeks)
Esophageal: Oral solution: 100-200 mg once daily for a minimum of 3 weeks; continue dosing for 2 weeks after resolution of symptoms
Coccidioidomycosis: 200 mg twice daily
Histoplasmosis: 200 mg 3 times/day for 3 days, then 200 mg twice daily (or once daily in mild-moderate disease) for 6-12 weeks in mild-moderate disease or ?12 months in progressive disseminated or chronic cavitary pulmonary histoplasmosis; in moderately-severe to severe infection, therapy should be initiated with ~2 weeks of a lipid formation of amphotericin B (Wheat, 2007)
Long-term suppression therapy: 200 mg/day (AIDSinfo guidelines, 2008)
Meningitis:
Coccidioides: 400-800 mg/day
Coccidioides, HIV-positive (unlabeled use): 200 mg 3 times/day for 3 days, then 200 mg twice daily; maintenance: 200 mg twice daily life-long (AIDSinfo guidelines, 2008)
Appropriate use: Fluconazole is preferred for meningeal infections.
Onychomycosis: 200 mg once daily for 12 consecutive weeks; alternative “pulse-dosing” may be considering for fingernail involvement only: 200 mg twice daily for 1 week; repeat 1-week course after 3-week off-time
Penicilliosis, HIV-positive (unlabeled use): 200 mg twice daily for 8-10 weeks (in severely-ill patients, initiate therapy with 2 weeks of amphotericin B); maintenance: 200 mg/day (AIDSinfo guidelines, 2008)
Pneumonia:
Coccidioides: Mild-to-moderate: 200 mg twice daily
Coccidioides, HIV-positive (focal pneumonia): 200 mg 3 times/day for 3 days, then 200 mg twice daily (AIDSinfo guidelines, 2008)
Protothecal infection: 200 mg once daily for 2 months
Sporotrichosis:
Lymphocutaneous: 100-200 mg/day for 3-6 months
Osteoarticular and pulmonary: 200 mg twice daily for 1-2 years (may use amphotericin B initially for stabilization)
Dosing adjustment in renal impairment: The FDA-approved labeling states to use with caution in patients with renal impairment. The following guidelines have been used by some clinicians:
Aronoff, 2007:
Clcr >10 mL/minute: No adjustment recommended
Clcr <10 mL/minute: Administer 50% of normal dose
Continuous renal replacement therapy (CRRT)/hemodialysis: 200 mg every 12 hours for 4 doses, then 200 mg every 24 hours (Heintz, 2009)
Hemodialysis: Not dialyzable
Dosing adjustment in hepatic impairment: Use caution in patients with hepatic impairment
Dental Usual Dosing
Oropharyngeal candidiasis: Adults: Oral solution: 200 mg once daily for 1-2 weeks; in patients unresponsive or refractory to fluconazole: 100 mg twice daily (clinical response expected in 1-2 weeks)
Administration: Oral
Doses >200 mg/day are given in 2 divided doses; do not administer with antacids. Capsule and oral solution formulations are not bioequivalent and thus are not interchangeable. Capsule absorption is best if taken with food, therefore, it is best to administer itraconazole after meals; solution should be taken on an empty stomach. When treating oropharyngeal and esophageal candidiasis, solution should be swished vigorously in mouth, then swallowed.
Monitoring Parameters
Liver function in patients with pre-existing hepatic dysfunction, and in all patients being treated for longer than 1 month; serum concentrations particularly for oral therapy (due to erratic bioavailability with capsule formulation); renal function
Reference Range
Serum concentrations may be performed to assure therapeutic levels. Itraconazole plus the metabolite hydroxyitraconazole concentrations should be >1 mcg/mL.
Timing of serum samples: Obtain level after ~2 weeks of therapy, level may be drawn anytime during the dosing interval.
Dietary Considerations
Capsule: Take with food.
Solution: Take without food, if possible.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. Take full course of medication, even if infection appears to be resolved; do not discontinue without consulting prescriber (treatment for some fungal infections may take several weeks or months). Take as directed; take capsule immediately after meals; take solution on empty stomach (1 hour before or 2 hours after meals). Do not take antacids or other medications within 1 hour before or 2 hours after itraconazole. Avoid grapefruit juice while taking this medication. Observe good hygiene measures to prevent reinfection. If you have diabetes, test serum glucose regularly (may affect response to oral hypoglycemics). Frequent blood tests may be required with prolonged therapy. May cause dizziness or drowsiness (use caution when driving or engaging in tasks that require alertness until response to drug is known); nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report new or unusual rash; any change in hearing acuity; difficulty breathing; chest pain; or other adverse reactions. Stop therapy and report immediately any signs and symptoms that may suggest liver dysfunction (eg, unusual fatigue, anorexia, nausea and/or vomiting, jaundice [yellowing of skin or sclera], dark urine, pale stool) so that the appropriate laboratory testing can be done. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber about appropriate contraceptive use; efficacy of oral contraceptives may be reduced. Breast-feeding is not recommended.
Geriatric Considerations
No specific data for the elderly. Transient or permanent hearing loss reported in the elderly; several reports include concurrent administration of quinidine.
Additional Information
Due to potential toxicity, the manufacturer recommends confirmation of diagnosis testing of nail specimens prior to treatment of onychomycosis.
Cardiovascular Considerations
Itraconazole has negative inotropic properties and cases of new heart failure or exacerbation of congestive heart failure have been reported. Itraconazole is contraindicated for the treatment of onychomycosis in patients with heart failure. The benefit:risk for therapy in the treatment of other types of fungal infections should be carefully considered in each patient, particularly those with heart failure and in heart transplant recipients. If indicated after cardiac, renal, or liver transplantation, itraconazole can increase cyclosporine levels by up to 50% at high doses. It also increases serum levels of lovastatin and simvastatin by up to 20-fold, as well as other HMG-CoA reductase inhibitors (except fluvastatin and rosuvastatin), by inhibiting CYP3A4. This is important since many post-transplantation patients are also hyperlipidemic and on HMG-CoA reductase inhibitors. Itraconazole may also increase levels of digoxin, disopyramide, dofetilide, and quinidine. The simultaneous administration of these medications may increase the risk of cardiotoxicity. Edema has been reported in patients concurrently receiving itraconazole and calcium channel blockers (CCBs). CCBs may cause additive negative inotropic effects when used concurrently with itraconazole. Use caution with concurrent use of itraconazole and CCBs due to an increased risk of CHF. Concurrent use of itraconazole and dofetilide, nisoldipine and quinidine is contraindicated.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Infectious Diseases Comment
In vitro resistance to itraconazole has been observed in C. krusei, C. glabrata and C. tropicalis isolates. These are generally the least susceptible Candida species.
Mental Health: Effects on Mental Status
May cause sedation
Mental Health: Effects on Psychiatric Treatment
Contraindicated with oral midazolam, pimozide, and triazolam
Nursing: Physical Assessment/Monitoring
Evaluate hepatic status and hypersensitivity history prior to treatment. Assess potential for interactions with other pharmacological or herbal products patient may be taking (eg, increased or decreased levels/effects and toxicity). Assess results of laboratory tests (LFTs), therapeutic effectiveness (resolution of fungal infection), and adverse reactions at regular intervals during therapy. Teach patient proper use (eg, necessity of taking full course of therapy), possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 100 mg
Sporanox®: 100 mg
Solution, oral:
Sporanox®: 100 mg/10 mL (150 mL) [cherry flavor]
Pricing: U.S. (www.drugstore.com)
Capsules (Itraconazole)
100 mg (28): $239.97
100 mg (30): $239.99
Capsules (Sporanox)
100 mg (30): $353.15
Capsules (Sporanox Pulsepak)
100 mg (28): $330.88
Solution (Sporanox)
10 mg/mL (150): $182.00
References
Ahmad SR, Singer SJ, and Leissa BG, “Congestive Heart Failure Associated With Itraconazole,” Lancet, 2001, 357(9270):1766-7.
Amichai B and Grunwald MH, “Adverse Drug Reactions of the New Oral Antifungal Agents - Terbinafine, Fluconazole, and Itraconazole,” Int J Dermatol, 1998, 37(6):410-5.
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007.
Chapman SW, Dismukes WE, Proia LA, et al, “Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America,” Clin Infect Dis, 2008, 46(12):1801-12.
Cleary JD, Taylor JW, and Chapman SW, “Itraconazole in Antifungal Therapy,” Ann Pharmacother, 1992, 26(4):502-9.
Cowie F, Meller ST, Cushing P, et al, “Chemoprophylaxis for Pulmonary Aspergillosis During Intensive Chemotherapy,” Arch Dis Child, 1994, 70(2):136-8.
De Backer M, De Vroey C, Lesaffre E, et al, “Twelve Weeks of Continuous Oral Therapy for Toenail Onychomycosis Caused by Dermatophytes: A Double-Blind Comparative Trial of Terbinafine 250 mg/day Versus Itraconazole 200 mg/day,” J Am Acad Dermatol, 1998, 38(5 Pt 3):S57-63.
Denning DW, Lee JY, Hostetler JS, et al, “NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis,” Am J Med, 1994, 97(2):135-44.
Grant SM and Clissold SP, “Itraconazole. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Superficial and Systemic Mycoses,” Drugs, 1989, 37(3):310-44.
“Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents,” June 18, 2008. Available at http://aidsinfo.nih.gov
Haria M, Bryson HM, and Goa KL, “Itraconazole: A Reappraisal of Its Pharmacological Properties and Therapeutic Use in the Management of Superficial Fungal Infections,” Drugs, 1996, 51(4):585-620.
Heintz BH, Matzke GR, Dager WE, “Antimicrobial Dosing Concepts and Recommendations for Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis,” Pharmacotherapy, 2009, 29(5):562-77.
Heymann WR and Manders SM, “Itraconazole-Induced Acute Generalized Exanthemic Pustulosis,” J Am Acad Dermatol, 1995, 33(1):130-1.
Jennings TS and Hardin TC, “Treatment of Aspergillosis With Itraconazole,” Ann Pharmacother, 1993, 27(10):1206-11.
Kauffman CA and Carver PL, “Antifungal Agents in the 1990s. Current Status and Future Developments,” Drugs, 1997, 53(4):539-49.
Kintzel PE, Rollins CJ, Yee WJ, et al, “Low Itraconazole Serum Concentrations Following Administration of Itraconazole Suspension to Critically Ill Allogenic Bone Marrow Transplant Recipients,” Ann Pharmacother, 1995, 29(2):140-3.
Lyman CA and Walsh TJ, “Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications,” Drugs, 1992, 44(1):9-35.
Mohr J, Johnson M, Cooper T, et al, “Current Options in Antifungal Pharmacotherapy,” Pharmacotherapy, 2008, 28(5):614-45.
Mouy R, Veber F, Blanche S, et al, “Long-Term Itraconazole Prophylaxis Against Aspergillus Infections in Thirty-Two Patients With Chronic Granulomatous Disease,” J Pediatr, 1994, 125(6 Pt 1):998-1003.
Neuvonen PJ and Suhonen R, “Itraconazole Interacts With Felodipine,” J Am Acad Dermatol, 1995, 33(1):134-5.
Neuvonen PJ, Backman JT, and Niemi M, “Pharmacokinetic Comparison of the Potential Over-The-Counter Statins Simvastatin, Lovastatin, Fluvastatin and Pravastatin,” Clin Pharmacokinet, 2008, 47(7):463-74.
Terrell CL, “Antifungal Agents. Part II. The Azoles,” Mayo Clin Proc, 1999, 74(1):78-100.
Tobon AM, Franco L, Espinal D, et al, “Disseminated Histoplasmosis in Children: The Role of Itraconazole Therapy,” Pediatr Infect Dis J, 1996; 15:1002-8.
Trepanier EF and Amsden GW, “Current Issues in Onchomycosis,” Ann Pharmacother, 1998, 32(2):204-14.
Tucker RM, Haq Y, Denning DW, et al, “Adverse Effects Associated With Itraconazole in 189 Patients on Chronic Therapy,” J Antimicrob Chemother, 1990, 26(4):561-6.
Varhe A, Olkkola KT, and Neuvonen PJ, “Oral Triazolam is Potentially Hazardous to Patients Receiving Systemic Antimycotics Ketoconazole or Itraconazole,” Clin Pharmacol Ther, 1994, 56(6 Pt 1):601-7.
Walsh TJ, Anaissie EJ, Denning DW, et al, “Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America,” Clin Infect Dis, 2008, 46(3):327-60.
Wheat J, Freifeld AG, Kleiman MB, et al, “Clinical Practice Guidelines for the Management of Patients With Histoplasmosis: 2007 Update by the Infectious Diseases Society of America,” Clin Infect Dis, 2007, 45(7):807–25.
Wheat J, Hafner R, Korzun AH, et al, “Itraconazole Treatment of Disseminated Histoplasmosis in Patients With the Acquired Immunodeficiency Syndrome,” Am J Med, 1995, 98(4):336-42.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2010
Content last modified January 2010
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