Posaconazole

Conditions
1. Prevention of Invasive Aspergillus or Candida
2. Oropharyngeal Candidiasis (including resistant to Itraconazole or Fluconazole)
3. Invasive pulmonary Aspergillosis (off-label)
Activity (similar activity to Voriconazole)
1. Aspergillus species
2. Blastomyces dermatitidis
3. Candida (most species, including Fluconazole resistant strains)
4. Coccidioides immitis
5. Cryptococcus neoformans
6. Dermatophytes or Tinea (Microsporum, Epidermophyton, Trichophyton)
7. Histoplasma capsulatum
8. Scedosporium apiospermum
9. Mucorales or Zygomycetes (e.g. Mucor species, Rhizopus species)
  1. Other azoles (including Voriconazole) have no significant activity against Mucorales

Azole Antifungal
1. Second generation triazole
2. Structurally similar to Itraconazole
Inhibits fungal CYP450 enzymes
Inhibits fungal sterol demethylation (selectively and strongly at 14-alpha demethylase)
1. Blocks the synthesis of plasma membrane steroids (conversion from lanosterol to ergosterol)
2. Results in plasma membrane damage

Oral Delayed Release Tablets: 100 mg
1. Take with food
2. Do not split, crush or chew
Oral Suspension: 40 mg/ml
1. Take within 20 minutes of a meal
Intravenous formulation: 300 mg/16.7 ml vials
1. First dose may be administered by peripheral IV ove 30 minutes
2. Subsequent doses should be via Central Line or PICC Line
3. Posaconazole's IV vehicle may accumulate in renal Impairment (GFR<50 ml/min)

Prevention of Invasive Aspergillus or Candida
1. Continued during period of severe Neutropenia or Immunosuppression
2. Suspension
  1. Take 200 mg (5 ml) of suspension orally three times daily
3. Delayed-Release Tablets
  1. Load 300 mg orally twice daily for first day
  2. Next, Take 300 mg orally daily
4. Injection
  1. Load 300 mg IV over 30 to 90 minutes (peripheral, PICC or Central Line) every 12 hours for first day
  2. Next, infuse 300 mg IV over 90 minutes via Central Line or PICC every 24 hours
Oropharyngeal Candidiasis
1. Load suspension 100 mg (2.5 ml) orally within 20 minutes of a meal twice daily on first day
2. Next, take suspension 100 mg (2.5 ml) orally within 20 minutes of a meal daily for 13 days
Resistant Oropharyngeal Candidiasis (refractory to Itraconazole or Fluconazole, IDSA guidelines)
1. Load suspension 400 mg (10 ml) orally within 20 minutes of a meal twice daily for 3 days
2. Next, take suspension 400 mg (10 ml) orally within 20 minutes of a meal daily for up to 28 days
Invasive pulmonary Aspergillosis (off-label, in adults)
1. Take 200 mg (5 ml) suspension orally four times daily until stable
2. Next, take 400 mg (10 ml) suspension orally twice daily for at least 6 to 12 weeks
3. Continued throughout Immunosuppression and until lesions resolve

Avoid in Lactation
Pregnancy
1. Avoid in first trimester
2. Skeletal malformations have been seen in animal studies
3. Unknown safety after first trimester

Oral Bioavailability
1. Significantly increased absorption and drug levels (up to 4 fold) when taken with a fatty meal
2. Alternatives if meals (including Nutritional Supplements) are not tolerated
  1. Take with a carbonated beverage (e.g. Ginger ale)
  2. Switch to delayed release tablet
Elimination Half-Life: 20 to 66 hours
1. Oral suspension levels >800 mg/day are unlikely to offer any additional benefit
Protein Binding: High
Metabolism
1. UDP Glucuronidation
2. P-gp Substrate and Inhibitor
3. CYP3A4 Inhibitor (strong)
Excretion
1. Stool: 71%
2. Urine: 13%

Agents that prolong QTc Interval (risk of Torsades de Pointes)
1. See Prolonged QT Interval due to Medication
2. Avoid CYP3A4 substrates that prolong QTc Interval
3. Pimozide
4. Quinidine
Agents that decrease oral suspension absorption (not delayed release tablets)
1. Cimetidine
  1. Other H2 Blockers and Antacids do not appear affected
2. Proton Pump Inhibitors
3. Metoclopramide
Other drugs that decrease Posaconazole levels
Posaconazole increases other drug levels
1. Posaconazole is a strong CYP3A4 Inhibitor
2. Atazanavir
3. Benzodiazepines
4. Cyclosporine
  1. Decrease Cyclosporine doses by 25% and monitor levels
5. Phenytoin
6. Rifabutin
7. Ritonavir
8. Sirolimus
9. Tacrolimus
  1. Decrease Tacrolimus doses by 66% and monitor levels
10. Vinca Alkaloids
  1. Consider decreasing Vinca Alkaloid dose (or avoiding coadministration)
Other drugs that are contraindicated with Posaconazole
1. Ergot Alkaloids
2. Halofantrine
3. Statins

Therapeutic drug levels
1. Especially consider if severe Vomiting, Diarrhea or medication delivery by NG tube