Itraconazole

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[edit] BRAND NAMES

[edit] STRUCTURE

Itraconazole.jpg

[edit] MECHANISM OF ACTION

Itraconazole is a triazole antifungal. It inhibits lanosterol 14α-demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol.

Ergosterol is an essential component of the fungal cell membrane. The inhibition of its synthesis results in accumulation of toxic 14α-methylated sterols and the production of a defective cell membrane with altered permeability and leakage of cellular contents.

Itraconazole has the same spectrum of action of Fluconazole, but also includes Aspergillus. However, it does not cross the BBB and cannot be used for the treatment of meningitis. It is known to be metabolised in the liver and also inhibits CYP450 enzymes especially CYP3A4.

[edit] INDICATIONS

  • Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:
    • Blastomycosis, pulmonary and extrapulmonary
    • Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis, and
    • 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 is also indicated for the treatment of the following fungal infections in non-immunocompromised patients:
    • Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium)
    • Onychomycosis of the fingernail due to dermatophytes (tinea unguium).
    • Oral and/or esophageal candidiasis: Itraconazole is a second choice drug for the treatment of oropharyngeal candidiasis after Fluconazole.

[edit] DOSAGE

Itraconazole should be administered after a full meal

  • Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.
  • Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended.
  • Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously.
    • IV Injection: the recommended intravenous dose is 200 mg twice a day, for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of Itraconazole Injection administered for greater than 14 days is not known. See complete prescribing information for Itraconazole Injection.
    • Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.
      Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.
  • Treatment of Onychomycosis:
    • Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.
    • Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without Itraconazole.
  • Oral and/or esophageal candidiasis: Oral solution: 100-200 mg/day for at least 3 weeks; continued for 2 weeks after symptom resolution. Swish in mouth 10 mL at a time for several seconds then swallow
  • Oral and/or esophageal candidiasis refractory to fluconazole: Oral solution: 100 mg twice a day for 2-4 weeks. Swish in mouth 10 mL at a time for several seconds then swallow

[edit] CONTRAINDICATIONS

  • Hypersensitivity to itraconazole
  • 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 unless the benefit clearly outweighs the risk. (Itraconazole shown to have a negative inotropic effect and has been associated with reports of congestive heart failure)
  • Coadministration of Itraconazole with CYP3A4 substrates for which increased plasma levels may result in serious or life-threatening reactions:
Drug Class
Drugs Within Class That Are Contraindicated With Itraconazole
Clinical Comment
Antiarrhythmics
dofetilide and quinidine
Potential for serious and/or life-threatening cardiac arrhythmia.
Ergot Derivatives
Dihydroergotamine, Ergotamine,Methylergonovine Potential for serious and/or life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent
Cisapride
Potential for serious and/or life threatening reactions such as cardiac arrhythmias.
HMG-CoA Reductase Inhibitors
Lovastatin, Simvastatin
Potential for serious reactions such as myopathy including rhabdomyolysis.
Neuroleptics
Pimozide
Potential for serious and/or life threatening reactions such as cardiac arrhythmias
Calcium channel blockers
Nisoldipine

Sedative/Hypnotics
Triazolam, oral Midazolam
Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression

[edit] WARNINGS AND PRECAUTIONS

  • 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, 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.
  • Life-threatening cardiac dysrhythmias, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), dofetilide or quinidine, concomitantly with Itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Itraconazole is contraindicated.

[edit] INTERACTIONS

  • HMG CoA-reductase inhibitors: Itraconazole inhibits the metabolism of HMG CoA-reductase inhibitors metabolized by CYP3A4 like atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Lovastatin and simvastatin, are contraindicated with Itraconazole
  • Calcium channel blockers: 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 nisoldipine is contraindicated
  • Anticonvulsants: carbamazepine, phenobarbital, phenytoin decrease plasma concentration of itraconazole
  • Antimycobacterials: isoniazid, rifabutin, rifampin decrease plasma concentration of itraconazole
  • Gastric Acid Suppressors/Neutralizers: antacids, H2-receptor antagonists, proton pump inhibitors decrease plasma concentration of itraconazole
  • Antineoplastics: Itraconazole may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.
  • Benzodiazepines: Concomitant administration of Itraconazole and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. (Concomitant administration of Itraconazole and oral midazolam or triazolam is contraindicated).
  • Immunosuppressants: Concomitant administration of Itraconazole and cyclosporine or tacrolimus increase plasma concentrations of these immunosuppressants. Concomitant administration of Itraconazole and sirolimus could increase plasma concentrations of sirolimus
  • Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine: Increase plasma concentration of itraconazole
  • Macrolide Antibiotics clarithromycin, erythromycin: Increase plasma concentration of itraconazole
  • Protease Inhibitors indinavir, ritonavir: Increase plasma concentration of itraconazole
  • Oral hypoglycemic agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents.
  • Warfarin: Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.

[edit] PREGNANCY AND LACTATION

Pregnancy Category C (US):: Itraconazole should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the 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. Effective contraception should be continued throughout Itraconazole therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported

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

[edit] SIDE EFFECTS

  • Most common adverse events: Nausea, vomiting, diarrhea, edema, fatigue, rash, pruritus, headache and hepatic function abnormal.
  • Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing period among patients being treated for onychomycosis and/or systemic fungal infections
  • Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
  • Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with Itraconazole

[edit] RELATED LINKS

Azoles mechanism of action

[edit] BIBLIOGRAPHY

[edit] REFERENCES

Antifungals
Ergosterol target : Cell membrane target Azoles (lanosterol 14 alpha-demethylase inhibitors) : Ergosterol inhibitors Imidazoles Topical: Bifonazole   Clotrimazole   Econazole   Fenticonazole   Ketoconazole   Isoconazole   Miconazole   Sertaconazole   Tioconazole
Triazoles Topical: Fluconazole   Terconazole
Systemic: Fluconazole   Itraconazole   Posaconazole   Voriconazole
Polyene antimycotics (ergosterol binding; they form pores in the membrane) Topical: Nystatin
Systemic: Amphotericin B
Allylamines (squalene epoxidase inhibitors) : Ergosterol inhibitors Topical: Amorolfine   Naftifine   Terbinafine
Systemic: Terbinafine
Echinocandins (β-glucan synthase inhibitors) : Cell wall target Anidulafungin   Caspofungin   Micafungin
Pyrimidine analogues / Thymidylate synthase inhibitors : Nucleic acid inhibitors Flucytosine
Mitotic inhibitors Griseofulvin
Others Ciclopirox