Itraconazole

Congestive Heart Failure (or ventricular dysfunction)
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)

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

Assumes nail testing confirming diagnosis before initiating systemic Antifungal
In women, start pulsed dosing on days 1-2 of Menstrual Cycle, and use reliable Contraception
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
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

General
1. Consider obtaining periodic drug levels in systemic fungal infection
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
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
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
Histoplasmosis Prophylaxis in HIV (off-label)
1. Take 200 mg orally once daily (monitor levels)
Coccidioidomycosis Suppression and Treatment in HIV (off-label)
1. Take 200 mg orally twice daily

Terbinafine is preferred over Itraconazole for Tinea Capitis treatment
NOT FDA approved in children
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
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

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
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
Long plasma Half-Life
1. Steady state reached within days
2. Risk of drug level accumulation
  1. Tissue concentrations are higher than plasma concentrations
Distribution
1. Poor CSF penetration
2. Poor urine penetration

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

General
1. CYP3A4 Substrate (affected by strong CYP3A4 inducers and CYP3A4 inhibitors)
2. CYP3A4 Inhibitor (strong)
3. P-Glycoprotein Inhibitor (P-gp inhibitor)
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)
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
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

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