Itraconazole

Aka: Itraconazole, Sporanox, Tolsura

advertisement

II. Indications

  1. Conditions
    1. Onychomycosis
    2. Tinea Capitis (off-label, second-line)
    3. Oropharyngeal Candidiasis (Thrush)
    4. Esophageal Candidiasis
    5. Blastomycosis
    6. Histoplasmosis
    7. Aspergillosis (second-line)
    8. Coccidioidomycosis (treatment and suppression in HIV Infection)
  2. Activity (broader activity than Fluconazole, but more limited distribution)
    1. Aspergillus species
    2. Blastomyces dermatitidis
    3. Candida (most species)
    4. Coccidioides species
    5. Cryptococcus neoformans
    6. Dermatophytes or Tinea (Microsporum, Epidermophyton, Trichophyton)
    7. Histoplasma capsulatum
    8. Paracoccidioides brasiliensis
    9. Sporothrix Species

III. Contraindications

  1. Congestive Heart Failure (or ventricular dysfunction)
  2. Resistant organisms
    1. Candida glabrata (some strains)
    2. Fusarium species
    3. Mucorales or Zygomycetes (e.g. Mucor species, Rhizopus species)
    4. Scedosporium species (variable activity)

IV. Mechanism

  1. Azole Antifungal (triazole)
  2. Inhibits fungal CYP450 enzymes
  3. Inhibits sterol demethylation
    1. Blocks the synthesis of plasma membrane steroids (conversion from lanosterol to ergosterol)
    2. Results in plasma membrane damage

V. Medications

  1. Intraconazole (standard formulation, Onmel, Sporanox)
    1. IV formulation is no longer available in U.S.
    2. Oral Capsules (Sporanox, taken with food): 100 mg
    3. Oral Tablets (Onmel): 200 mg
    4. Oral Solution (Sporanox, taken on an empty Stomach): 10 mg/ml
      1. Preferred in oral and Esophageal Candidiasis
      2. In Cystic Fibrosis, oral solution may not achieve adequate serum levels
  2. Tolsura Capsules
    1. Available as 65 mg capsules
      1. Itraconazole 200 mg is equivalent to 130 mg Tolsura
      2. Not interchangeable with other formulations
    2. Higher Bioavailable formulation (greater GI absorption) released in 2019
      1. Take with food
      2. Do not crush, cut or chew
    3. Indications
      1. Blastomycosis
      2. Histoplasmosis
      3. Aspergillosis
    4. Precautions
      1. Increased serum levels with acid suppression (e.g. Proton Pump Inhibitor)
      2. Five fold higher cost than Itraconazole ($70/day instead of $15/day)
    5. References
      1. (2019) Presc Lett 26(2): 9

VI. Dosing: General

  1. Lower pH increases absorption
  2. Take oral capsules with food
  3. Take oral solution on an empty Stomach
  4. Monitor for hepatotoxicity (see below)

VII. Dosing: Onychomycosis

  1. Assumes nail testing confirming diagnosis before initiating systemic Antifungal
  2. In women, start pulsed dosing on days 1-2 of Menstrual Cycle, and use reliable Contraception
  3. Fingernails
    1. Daily (continuous): 200 mg orally daily for 6 weeks
    2. Monthly (pulsed): 200 mg orally twice daily for first week of each month for 2 to 3 months
  4. Toenails
    1. Daily (continuous): 200 mg orally daily for 12 weeks
    2. Monthly (pulsed): 200 mg orally twice daily for first week of each month for 3 to 4 months

VIII. Dosing: Systemic Fungal Infections

  1. General
    1. Consider obtaining periodic drug levels in systemic fungal infection
  2. Oropharyngeal Candidiasis (Thrush)
    1. Second-line agent in Immunocompromised adults with concurrent esophageal involvement
    2. Adult: 200 mg oral solution daily (or divided twice daily) for 1 to 2 weeks (up to 4 weeks)
    3. Child (age >5 years, off-label): 2.5 mg/kg oral solution twice daily (max 200 to 400 mg/day) for 7 to 14 days
  3. Esophageal Candidiasis
    1. Swish and swallow solution on empty Stomach
    2. Adult: 100 to 200 mg oral solution daily for 3 weeks and for at least 2 weeks after symptoms resolve
    3. Child (age >5 years, off-label): 2.5 mg/kg oral solution twice daily (or 5 mg/kg once daily) for 21 days
      1. Maximum 200 to 400 mg/day
  4. Blastomycosis, Histoplasmosis (and second-line in Aspergillosis) in Adults
    1. Sporanox or Onmel
      1. Take 200 mg orally once to twice daily with full meal for up to 3 months
      2. In severe infections, start 200 mg orally three times daily for up to 3 days
    2. Tolsura
      1. Take 130 mg orally once daily (or divided twice daily) for up to 3 months
      2. May increase dose in 65 mg (1 capsule) increments up to 260 mg/day if needed
      3. In Aspergillosis, may give 130 mg orally once to twice daily
        1. May load 130 mg orally three times daily for up to 3 days
  5. Histoplasmosis Prophylaxis in HIV (off-label)
    1. Take 200 mg orally once daily (monitor levels)
  6. Coccidioidomycosis Suppression and Treatment in HIV (off-label)
    1. Take 200 mg orally twice daily

IX. Dosing: Tinea Capitis

  1. Terbinafine is preferred over Itraconazole for Tinea Capitis treatment
  2. NOT FDA approved in children
  3. Daily
    1. Solution 3 mg/kg/day up to 500 mg/day for 4-6 weeks
    2. Capsules 5 mg/kg/day up to 500 mg/day for 4-6 weeks
  4. Monthly
    1. Solution 3 mg/kg/day up to 500 mg/day, daily for one week per month for 2-3 months
    2. Capsules 5 mg/kg/day up to 500 mg/day, daily for one week per month for 2-3 months

X. Pharmacokinetics

  1. Metabolism
    1. Hepatic metabolism (Cytochrome P450) to inactive metabolites
    2. Excretion in urine and stool
    3. Levels are affected by hepatic Impairment
      1. Not affected by renal Impairment or Hemodialysis
  2. Oral Bioavailability
    1. Requires acidic gastric environment
    2. Oral solution (taken on an empty Stomach) has greater Bioavailability than oral capsules (taken with food)
    3. Peak levels within 4 hours
  3. Long plasma Half-Life
    1. Steady state reached within days
    2. Risk of drug level accumulation
      1. Tissue concentrations are higher than plasma concentrations
  4. Distribution
    1. Poor CSF penetration
    2. Poor urine penetration

XI. Adverse Effects

  1. Serious
    1. Hepatotoxicity (increased serum Aminotransferases)
      1. May occur even within first week of dosing
      2. Consider monitoring Liver Function Tests in all patients (see below)
    2. Stevens Johnson Syndrome
    3. Pulmonary Edema or Congestive Heart Failure (rare)
      1. Itraconazole may have negative inotrope activity
  2. Common
    1. Nausea or Vomiting
    2. Diarrhea
  3. Uncommon
    1. Peripheral Neuropathy
    2. Vision changes
    3. Hearing Loss
    4. Tinnitus
    5. Hypokalemia
    6. Adrenal Insufficiency
    7. Rhabdomyolysis

XII. Safety

  1. Avoid in Lactation
  2. Pregnancy
    1. Pregnancy Category X in first trimester (avoid)
    2. Unknown safety in second and third trimesters

XIII. Drug Interactions

  1. General
    1. CYP3A4 Substrate (affected by strong CYP3A4 inducers and CYP3A4 inhibitors)
    2. CYP3A4 Inhibitor (strong)
    3. P-Glycoprotein Inhibitor (P-gp inhibitor)
  2. QTc Prolongation risk with other CYP3A4 Substrates (risk of Torsades de Pointes)
    1. See Prolonged QT Interval due to Medication
    2. Astemizole
    3. Cisapride
    4. Quinidine
    5. Pimozide (Orap)
  3. INCREASES other drug levels (toxicity risk)
    1. HMG-CoA Reductase Inhibitors (Lovastatin)
      1. Simvastatin
      2. Lovastatin
      3. Rhabdomyolysis Risk
    2. Benzodiazepines (significant sedation)
      1. Midazolam (Versed)
      2. Triazolam (Halcion)
      3. Avoid other Benzodiazepines also
      4. Avoid Barbiturates (e.g. Phenobarbital)
    3. Oral Hypoglycemics (e.g. Sulfonylureas)
      1. Risk of Hypoglycemia
    4. Warfarin
      1. Increased bleeding risk
    5. Agents to avoid in renal or hepatic Impairment
      1. Colchicine
      2. Fesoterodine
      3. Solifenacin
    6. Other agents with increased drug levels (avoid with these agents)
      1. Cyclosporine
      2. Digoxin
      3. Disopyramide
      4. Dofetilide
      5. Dronedarone
      6. Eplerenone
      7. Ergot alkaloids
      8. Irinotecan
      9. Ivadrabine
      10. Lurasidone
      11. Methadone
      12. Nisoldipine
      13. Phenytoin
      14. Ranolazine
      15. Ticagrelor
  4. Agents that DECREASE Itraconazole levels
    1. Medications raising gastric pH and lowering Itraconazole absorption
      1. Antacids
      2. H2 Blockers (e.g. Ranitidine, Felodipine)
      3. Proton Pump Inhibitors (e.g. Omeprazole)
    2. CYP3A4 Inducers
      1. Carbamazepine
      2. Isoniazid
      3. Phenobarbital
      4. Phenytoin
      5. Rifampin

XIV. Monitoring: Onychomycosis

  1. Pulse therapy: no monitoring
  2. Continuous therapy: Labs at baseline (previously also recommended every 6 weeks)
    1. Aspartate Aminotransferase (AST)
    2. Alanine Aminotransferase (ALT)

XV. Resources

  1. Itraconazole Capsule (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ab38a8a-3708-4b97-9f7f-8e554a15348d
  2. Itraconazole Solution (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=43ded1aa-f825-40fe-aa9a-addd36a07f06
  3. Tolsura (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=306352d1-9d5a-49ad-b72d-893b99546861

XVI. References

  1. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  2. (2012) Med Lett Drugs Ther 10(120): 61-8 [PubMed]
  3. (1993) Med Lett Drugs Ther 35(888): 7-9 [PubMed]
  4. Boogaerts (2001) Drugs 61(Suppl I):39-47 [PubMed]
  5. De Beule (2001) Drugs 61(Suppl I):27-37 [PubMed]
  6. De Doncker (1997) J Am Acad Dermatol 37:969-74 [PubMed]
  7. Ely (2014) Am Fam Physician 90(10): 702-10 [PubMed]
  8. Friedlander (1999) Pediatr Infect Dis J 18(2):205-10 [PubMed]
  9. Gupta (1998) Int J Dermatol 37:303-8 [PubMed]
  10. Gupta (1999) J Am Acad Dermatol 41:237-49 [PubMed]
  11. Gupta (2001) Eur J Dermatol 11(1):6-10 [PubMed]

Images: Related links to external sites (from Bing)

These images are a random sampling from a Bing search on the term "Itraconazole." Click on the image (or right click) to open the source website in a new browser window. Search Bing for all related images

Related Studies

Cost: Medications

itraconazole (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ITRACONAZOLE 10 MG/ML SOLUTION Generic $1.35 per ml
ITRACONAZOLE 100 MG CAPSULE Generic $0.88 each
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information. GoodRx is another tool for finding lower drug prices.

Related Topics in Pharmacology

advertisement