Posac

Approved Indications:

• Prophylaxis of Invasive Fungal Infections in:
• Patients ≥13 years old with prolonged neutropenia due to chemotherapy for hematologic malignancies (e.g., AML, MDS)
• Hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) at high risk for fungal infections
• Treatment of Oropharyngeal Candidiasis (including refractory cases)
• Initial oropharyngeal candidiasis
• Fluconazole- or itraconazole-refractory oropharyngeal candidiasis
• Treatment of Invasive Fungal Infections (Salvage Therapy):
• Invasive aspergillosis
• Fusariosis
• Zygomycosis
• Chromoblastomycosis
• Mycetoma
• Coccidioidomycosis

Off-Label/Clinically Accepted Uses:

• Treatment of mucormycosis when first-line therapies (e.g., amphotericin B) are not tolerated or ineffective
• Prophylaxis in pediatric patients (<13 years) under clinical discretion
• Use in solid organ transplant recipients for invasive fungal prophylaxis

Dosage Forms:

• Delayed-release tablets
• Oral suspension
• Intravenous injection

Prophylaxis of Invasive Fungal Infections (≥13 years):

• Delayed-release tablets:
  300 mg twice daily on Day 1, then 300 mg once daily thereafter
• IV injection:
  300 mg twice daily on Day 1, then 300 mg IV once daily
• Oral suspension:
  200 mg three times daily

Treatment of Oropharyngeal Candidiasis:

• Initial cases (oral suspension):
  100 mg once daily on Day 1, then 100 mg once daily for 13 days
• Refractory cases:
  400 mg oral suspension twice daily

Pediatric Use:

• Not FDA-approved for patients <13 years, but off-label use under specialist supervision may follow weight-based dosing with close monitoring.

Hepatic Impairment:

• Use with caution in moderate to severe hepatic impairment; monitor liver function. No specific dose adjustment, but reduced clearance may occur.

Renal Impairment:

• Oral dosage: No adjustment needed.
• IV formulation: Avoid in severe renal impairment (CrCl <50 mL/min) due to accumulation of IV vehicle (cyclodextrin).

Administration Notes:

• Delayed-release tablets and IV: With or without food
• Oral suspension: Should be taken with a full meal or nutritional supplement for optimal absorption
• Do not interchange dosage forms due to differing pharmacokinetics

Posaconazole is a triazole antifungal agent that inhibits the enzyme lanosterol 14α-demethylase, part of the cytochrome P450 system in fungal cells. This inhibition blocks the conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. The resulting depletion of ergosterol and accumulation of toxic sterol precursors compromises membrane integrity, leading to increased permeability, leakage of cellular contents, and ultimately fungal cell death. Its broad-spectrum activity includes Candida spp., Aspergillus spp., and rare molds like Mucorales.

• Absorption:
• Oral suspension has variable absorption; enhanced significantly by high-fat meals
• Delayed-release tablets have improved bioavailability and reduced variability
• Peak Plasma Time:
• Tablets: ~5 hours
• Suspension: ~3–5 hours
• Bioavailability:
• Suspension: Variable (~8–47%)
• Tablets: Higher and more consistent
• Distribution:
• Highly protein-bound (>98%)
• Large volume of distribution (~1774 L)
• Metabolism:
• Primarily via UDP-glucuronidation (UGT1A4); minor CYP450 involvement
• Half-life:
• Approximately 25–35 hours
• Excretion:
• Mainly in feces (~77%) as unchanged drug
• <20% via urine

• Pregnancy:
• FDA Pregnancy Category: Not assigned under PLLR system
• Animal studies show fetal toxicity at high doses. No well-controlled human studies. Use only if benefits outweigh potential risks. Avoid use during pregnancy unless clearly necessary.
• Lactation:
• Unknown if excreted in human milk. Due to potential for serious adverse reactions in the infant, a decision should be made to discontinue either the drug or breastfeeding.
• Contraception:
• Advise effective contraception during treatment and for at least 90 days after the last dose due to possible fetal harm.

• Primary Class: Antifungal Agent
• Subclass: Broad-spectrum Triazole Antifungal
• Generation: Second-generation triazole

• Known hypersensitivity to posaconazole or any component of the formulation
• Co-administration with:
• Sirolimus
• Pimozide
• Quinidine
• Certain statins (e.g., simvastatin, lovastatin)
• Ergot alkaloids (e.g., ergotamine)
• Due to risk of QT prolongation and serious arrhythmias

• QT Prolongation:
• Risk of torsades de pointes. Correct electrolyte imbalances (e.g., hypokalemia) before treatment. Avoid with other QT-prolonging agents.
• Hepatotoxicity:
• Elevations in ALT/AST, rare cases of hepatic failure. Monitor liver function tests before and during therapy.
• Drug Absorption Variability (Oral Suspension):
• Food intake and GI function significantly affect absorption. Avoid use in patients with severe diarrhea, vomiting, or mucositis.
• Superinfections:
• Prolonged use may lead to resistant fungal or bacterial infections.
• Hypersensitivity Reactions:
• Including anaphylaxis, angioedema, and urticaria
• Use in Pediatric Populations:
• Not well-studied; caution advised

Common Adverse Effects (≥10%):

• Gastrointestinal:
• Nausea, vomiting, diarrhea, abdominal pain
• Liver:
• Elevated ALT, AST, alkaline phosphatase, bilirubin
• Hematologic:
• Anemia, neutropenia, thrombocytopenia
• General:
• Headache, fatigue, fever

Serious Adverse Effects:

• QT prolongation and torsades de pointes
• Hepatic failure
• Anaphylactic reactions
• Severe skin reactions (rare)

Onset & Severity:

• GI and liver enzyme changes often appear in the first 1–2 weeks
• QT prolongation may occur early and may be dose-dependent

• CYP3A4 Inhibition:
• Strong inhibitor; increases serum levels of CYP3A4 substrates (e.g., tacrolimus, cyclosporine, sirolimus)
• May require dosage reduction or avoidance of concurrent use
• Gastric pH-Altering Agents:
• Proton pump inhibitors, H2 blockers may reduce suspension absorption; minimal effect on delayed-release tablets
• QT-Prolonging Drugs:
• Additive effect—avoid combining with pimozide, quinidine, or certain antipsychotics
• Statins (Simvastatin, Lovastatin):
• Contraindicated due to rhabdomyolysis risk from elevated statin levels
• Immunosuppressants (Cyclosporine, Tacrolimus):
• Dose adjustment and therapeutic drug monitoring necessary

• Delayed-Release Tablets & IV Preferred Over Suspension due to improved and consistent absorption, especially in severely ill or neutropenic patients
• NCCN and IDSA Guidelines:
• Recommend posaconazole for prophylaxis in high-risk hematologic malignancies and salvage treatment of refractory aspergillosis/mucormycosis
• Formulation Guidance:
• Do not substitute suspension for tablets or IV on a mg-to-mg basis

• Oral Suspension:
• Store at 2°C to 8°C (36°F to 46°F).
• Once opened, can be stored at room temperature (up to 25°C) for up to 30 days
• Delayed-Release Tablets:
• Store at 20°C to 25°C (68°F to 77°F); protect from moisture
• IV Formulation:
• Store at 2°C to 8°C (36°F to 46°F). Do not freeze.
• Once diluted, use within 24 hours if stored at room temperature
• Handling:
• Shake suspension before use
• Do not crush or break tablets
• Use aseptic technique for IV preparation