1. Noxafil
2. SCH-56592

• A. IMPORTANT NOTE
  
  • 1. Posaconazole should be taken with a food (preferably containing fat) to ensure maximal absorption (Courtney et al, 2003).
• B. ORAL
  
  • 1. FUNGAL INFECTIONS
    
    • a. Oral posaconazole doses of 800 milligrams/day (in two or four divided doses) have been used in the treatment of treatment of various fungal infections (ie, aspergillosis, candidiasis, cryptococcosis, fusariosis, and/or other fungal infections) in immunocompromised patients refractory to or intolerant of conventional antifungal therapy (Anon, 2003).
• C. OPHTHALMIC
  
  • 1. FUSARIUM SOLANI KERATITIS
    
    • a. Oral and topical posaconazole has been used in the treatment of Fusarium solani keratitis and endophthalmitis at an initial oral dose of 200 milligrams (mg) four times daily in combination with hourly topical ocular application of posaconazole suspension ( 10 mg/0.1 milliliter)(Sponsel et al, 2002).

• A. Safety and efficacy have not been established in pediatric patients. Data are lacking.

• A. TIME TO PEAK CONCENTRATION :
  
  • 1. Oral: single dose, 5.8 to 8.8 hours; multiple dose, 4 to 11 hours (Courtney et al, 2003).
    • a. Mean maximum concentrations of 113 to 1,320 nanograms/milliliter were observed at a mean of 5.8 to 8.8 hours following the administration of single oral doses of posaconazole (50 to 1,200 milligrams) in healthy subjects. The plasma posaconazole levels increased proportionally between the 50 and 800 mg dosage range, however, plasma concentrations at the 1,200 mg dose were equal to or lower than concentrations observed at the 800 mg dose indicating saturation of absorption above the 800 mg dose (Courtney et al, 2003).
    • b. During twice-daily dosing of posaconazole (100 to 800 milligrams/day) over 14 days, mean peak plasma concentrations were achieved on day one at 5 hours and 8 hours following the administration of the first and second doses, respectively. On day 14, peak plasma concentrations (457 to 4,150 nanograms/milliliter) were observed at 4 to 6 hours and at 9 to 11 hours following the administration of the first and second doses, respectively (Courtney et al, 2003).
    • c. Under fed conditions, mean maximum concentrations of 378 to 512 nanograms/milliliter were observed at a mean of 4.1 to 5.5 hours following the administration of single oral 200 milligram doses of posaconazole in healthy subjects (Courtney et al, 2003a).
    • d. Steady state concentrations of posaconazole are achieved by day 10 of twice daily dosing (100 to 800 milligrams/day) (Courtney et al, 2003).
• B. AREA UNDER THE CURVE : single dose (2,501 to 49,841 ng x hr/mL); multiple dose (8,295 to 73,105 ng x hr/mL) (Courtney, 2003).
  • 1. Area under the curve (zero to infinity) was 2,501 to 49,841 nanograms x hour/milliliter (ng x hr/mL) following 50 to 1200 milligram single oral doses of posaconazole in healthy subjects (Courtney, 2003).
  • 2. Area under the curve (0 to 24 hours) was 8,295 to 73,105 nanograms x hour/milliliter following 14 days of twice daily oral doses of posaconazole (100 to 800 milligrams/day) in healthy subjects (Courtney, 2003).

• A. BIOAVAILABILITY (F) :
  
  • 1. Oral, well-absorbed (Courtney et al 2003a).
• B. EFFECTS OF FOOD : enhanced absorption (Courtney et al, 2003a).
  • 1. In healthy subjects who received 200-milligram doses of posaconazole tablets or suspension, food intake enhanced the rate and extent of absorption. When taken with food, the oral suspension increased the mean posaconazole area-under-the curve (AUC) (0 to 72 hours) by 37% and maximum plasma concentration (C-MAX) by 23%, as compared with the tablet formulation. A four-fold increase in both the mean AUC (0 to 72 hours) and C-MAX values was observed when posaconazole suspension was administered with a high-fat meal as compared with administration while fasted (relative AUC (0 to 72 hours) 90% CI = 343% to 448%; C-MAX 90% CI = 352% to 493%; both values, p less then 0.001). However, administration of the suspension with a non-fat meal also increased exposure as indicated by a 2.6-fold increase in mean AUC (0 to 72 hours) (90% CI = 231% to 302%) and a three-fold increase in C-MAX (90% CI = 250% to 350%) as compared with the fasted state (p less than 0.001, both values) (Courtney et al, 2003a).
  • 2. The administration of antacid with 200 milligrams of posaconazole in fasted and non-fasted healthy adults increased the relative oral bioavailability by 15% in fasted volunteers and decreased the relative oral bioavailability by 12% in non-fasted volunteers, however, these changes were not statistically or clinically significant (Courtney et al, 2004).
  • 3. Under fed conditions, mean maximum concentrations of 378 to 512 nanograms/milliliter were observed at a mean of 4.1 to 5.5 hours following the administration of single oral 200 milligram doses of posaconazole in healthy subjects (Courtney et al, 2003a).

• 2.3.2.1 DISTRIBUTION SITES
  • A. TOTAL PROTEIN BINDING : 98 to 99% (Courtney et al, 2003).
    • 1. Following single and multiple oral doses of posaconazole (50 to 1200 milligrams/day) in healthy volunteers, the mean apparent volume of distribution ranged from 343 to 1,341 liters (Courtney et al, 2003).
• 2.3.2.2 DISTRIBUTION KINETICS

• 2.3.3.1 METABOLISM SITES AND KINETICS
  • A. LIVER, primary (Herbrecht, 2004).
    • 1. Posaconazole is primarily metabolized in the liver, where is undergoes glucuronidation and is transformed into biologically inactive metabolites (Herbrecht, 2004).
• 2.3.3.2 METABOLITES
  • A. Biologically active metabolites of posaconazole have not been detected in human plasma (Kim et al, 2003).

• 2.3.4.1 BREAST MILK
  • A. BREASTFEEDING : Unknown
    • 1. It is not known if posaconazole is excreted into human breast milk. Data are lacking.
• 2.3.4.2 KIDNEY
  • A. RENAL EXCRETION : 14% (Herbrecht, 2004).
    • 1. Approximately 14% of an administered dose is excreted in the urine as multiple glucuronidated derivatives. Minor amounts are eliminated in the urine as parent compound (Herbrecht, 2004).
• 2.3.4.3 OTHER
  • A. TOTAL BODY CLEARANCE : A dose-dependent clearance has been observed with total body clearance values ranging from 4.1 to 6.6 milligrams/minute/kilogram following the administration of singe oral doses of 50 to 1,200 milligrams (Courtney et al, 2003).
    • 1. A dose-dependent clearance has been observed with total body clearance values ranging from 4.1 to 6.6 milligrams/minute/kilogram following the administration of singe oral doses of 50 to 1,200 milligrams (Courtney et al, 2003).
  • B. OTHER EXCRETION :
    
    • 1. Feces, 77% (Herbrecht, 2004).
      • a. Seventy-seven percent of an administered dose is excreted in the feces as parent compound (Herbrecht, 2004).

• 2.3.5.1 PARENT COMPOUND
  • A. ELIMINATION HALF-LIFE : 16 to 31 hours (Courtney et al, 2003).
    • 1. Following the administration of single 200 to 1200 milligram oral doses of posaconazole in healthy volunteers, the mean half-life was 25 hours; however, the half-lives following the administration of single 50 and 100 milligram oral doses were 16 and 18 hours, respectively (Courtney et al, 2003).
    • 2. Following multiple oral doses of posaconazole (50 to 400 milligrams twice daily) in healthy volunteers, the mean elimination half-life was 19 to 31 hours (Courtney et al, 2003).
    • 3. In healthy men, the elimination half-life was approximately 22 hours following single oral 200 milligram doses of posaconazole regardless of formulation (tablet or suspension) or food intake (Courtney et al, 2003a).

• A. CARDIOVASCULAR EFFECTS
  
  • 1. HYPOTENSION occurred in 6% of immunocompromised patients following the administration of posaconazole (800 milligrams/day in divided doses) for the treatment of mycoses refractory or intolerant to conventional antifungal therapy (Anon 2003).

• A. CENTRAL NERVOUS SYTEM EFFECTS
  
  • 1. FATIGUE, HEADACHE, SOMNOLENCE, and DIZZINESS have occurred in at least 10% of patients following the administration of posaconazole, regardless of causality (Courtney et al, 2004; Anon 2003; Courtney et al, 2003; Courtney et al, 2003a).
  • 2. Six percent of immunocompromised patients experienced CONFUSION following the administration of posaconazole (800 milligrams/day in divided doses) for the treatment of mycoses refractory or intolerant to conventional antifungal therapy (Anon 2003).

• A. GASTROINTESTINAL EFFECTS
  
  • 1. CONSTIPATION and DRY MOUTH have occurred in at least 10% of posaconazole-treated patients, regardless of causality (Courtney et al, 2003).
  • 2. DIARRHEA (12%), ABDOMINAL PAIN (9%), NAUSEA (7%), and VOMITING (7%) occurred in immunocompromised patients following the administration of posaconazole (800 milligrams/day in divided doses) for the treatment of mycoses refractory or intolerant to conventional antifungal therapy (Anon 2003).

• A. GENITOURINARY EFFECTS
  
  • 1. URINARY TRACT INFECTION (2%) has been reported following the administration of posaconazole in HIV-positive patients with oropharyngeal candidiasis (Anon, 2003).
  • 2. VAGINITIS (2%) has been reported following the administration of posaconazole in HIV-positive women with oropharyngeal candidiasis (Anon, 2003).

• A. CUTANEOUS EFFECTS
  
  • 1. RASH (2%) has been reported following the administration of posaconazole in HIV-positive patients with oropharyngeal candidiasis (Anon, 2003).

• A. MUSCULOSKELETAL EFFECTS
  
  • 1. MUSCULOSKELETAL PAIN occurred in 7% of immunocompromised patients following the administration of posaconazole (800 milligrams/day in divided doses) for the treatment of mycoses refractory or intolerant to conventional antifungal therapy (Anon 2003).

• A. OVERDOSE
  
• B. FEVER
  
  • 1. Fever occurred in 12% of immunocompromised patients following the administration of posaconazole (800 milligrams/day in divided doses) for the treatment of mycoses refractory or intolerant to conventional antifungal therapy (Anon 2003).

• 1. Effects in human pregnancy are unknown. Data are lacking.

• A. LABORATORY PARAMETERS
  
  • 1. Culture/sensitivity of suspected fungal pathogens
• B. PHYSICAL EXAMINATION
  
  • 1. Clinical/radiographic resolution of signs/symptoms of infection.

• 1. Posaconazole is a triazole antifungal agent that possesses structural similarities to itraconazole, however, it is a single isomer with fewer sites of metabolism. Posaconazole inhibits fungal ergosterol synthesis through inhibition of lanosterol 14-alpha demethylase and is highly selective for fungal cytochrome P450 systems. In contrast to other azole antifungals, posaconazole is not extensively metabolized by CYP450 enzymes (Anon, 2003; Courtney et al, 2003; Herbrecht, 2004).

• 1. Posaconazole minimum inhibitory concentrations at the 90% level against isolates of the Candida species were as follows: C albicans (fluconazole- and itraconazole-resistant), 1 mcg/mL; C glabrata, 4 mcg/mL; C krusei, 1 mcg/mL; C lusitaniae, 0.06 mcgmL; C parapsilosis, 0.5 mcg/mL; and C tropicalis, 0.25 mcg/mL. Posaconazole minimum inhibitory concentrations at the 90% level against Cryptococcus neoformans was 0.25 mcg/mL (Anon, 2003).
• 2. In vitro, posaconazole minimum inhibitory concentration at the 90% level against Aspergillus fumigatus was 0.03 mcg/mL (Anon, 2003).
• 3. In an in vitro study, posaconazole had an overall minimum inhibitory concentration at the 90% level of 1 mcg/mL against 36 isolates of Zygomycetes (Tobon et al, 2003).
• 4. Posaconazole minimum inhibitory concentrations at 24 and 48 hours against amphotericin B-resistant Fusarium species were 1 mcg/mL and 8 mcg/mL, respectively (Sponsel et al, 2002).

• 1. In vitro tests have shown posaconazole to be active against Candida species, (including C albicans, C glabrata, C krusei, C tropicalis, and C parapsilosis, C lusitaniae, C dubliniensis, C pelliculosa, C guilliermondii, and C famata), and Aspergillus species (including A fumigatus, A flavus, A niger, A versicolor, and A terreus). Posaconazole has also exhibited in vitro activity against rare and emerging fungal pathogens such as Coccidioides immitis, Fusarium, Histoplasma, Zygomycetes, phaeohyphomycetes and other filamentous fungi. In addition, posaconazole has demonstrated activity against fluconazole- and itraconazole-resistant Candida species, itraconazole-, voriconazole-, and amphotericin B-resistant Aspergillus fumigatus, luconazole-resistant C neoformans and Zygomycetes (Herbrecht, 2004).

• 1. The pharmacokinetics, efficacy and safety profile of posaconazole are reviewed (Herbrecht, 2004).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, no; pediatric, no
  EFFICACY: Adult, possibly effective
  DOCUMENTATION: Adult, poor
  

• 2. SUMMARY :

  
   - Posaconazole was used successfully in the 
     treatment of disseminated aspergillosis in a 
     lung transplant patient after failing therapy 
     with itraconazole and amphotericin B lipid 
     complex
  

• 3. ADULT : A bilateral lung transplant patient with disseminated aspergillosis was successfully treated with posaconazole after failing therapy with itraconazole and amphotericin B lipid complex. The 64-year-old male patient was treated with oral posaconazole suspension (400 milligrams twice daily) after failing itraconazole and amphotericin B lipid complex therapy for treatment of an Aspergillus fumigatus infection, which disseminated from the lung to the ankle and adjacent bone. Following six months of therapy, the patient's ankle did not exhibit any evidence of osteomyelitis or soft tissue infection, small focal fluid collections had resolved, and the lungs were clear. Posaconazole therapy was continued for 12 months, with no evidence of recurrent infection at the end of the treatment period. No adverse effects were observed during treatment (Lodge et al, 2004).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, no; pediatric, no
  EFFICACY: Adult, possibly effective
  DOCUMENTATION: Adult, fair
  

• 2. SUMMARY :

  
   - Posaconazole has been used in the treatment of 
     treatment of various fungal infections in 
     immunocompromised patients refractory to
     conventional therapy
  

• 3. ADULT : Posaconazole therapy appeared to be effective in the treatment of various fungal infections in immunocompromised patients refractory to conventional antifungal therapy. In an open label, non-comparative, multicenter trial, immunocompromised patients (n=80) with aspergillosis, candidiasis, cryptococcosis, fusariosis, and/or other fungal infections who were refractory to or intolerant of conventional antifungal therapy received posaconazole for up to 12 months at a dose of 800 milligrams/day (four divided doses while hospitalized, then two divided doses after discharge). Complete or partial response was observed at 4 weeks in 50% (11/22) of patients with aspergillosis, 80% (8/10) of patients with candidiasis, 80% (4/5) of patients with fusariosis, 58% (7/12) of patients with cryptococcosis, and 74% (14/19) of patients with other infections. At 8 weeks, responses continued in 75% (12/16), 63% (5/8), 50% (2/4), 45% (5/11), and 44% (8/18) of patients with aspergillosis, candidiasis, fusariosis, cryptococcosis and other infections, respectively (Anon, 2003).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, no; pediatric, no
  EFFICACY: Adult, possibly effective
  DOCUMENTATION: Adult, poor
  

• 2. SUMMARY :

  
   - Posaconazole was useful in the treatment of 
     Fusarium solani keratitis progressing to 
     endophthalmitis in one case report
  

• 3. ADULT :
  
  • a. Oral and topical posaconazole therapy was useful in the treatment of Fusarium solani keratitis and endophthalmitis in a healthy female patient. While wearing cosmetic soft contact lenses, a 42-year old woman developed amphotericin B resistant Fusarium solani keratitis in her left eye, which progressed to endophthalmitis. After failing therapy with amphotericin B, natamycin, cefazolin, neosporin, and atropine; the lesion spread to much of the corneal periphery. Approximately one month following initial presentation, the patient's anterior chamber was filled with fibrin, with a central corneal descemetocele and almost complete corneal infiltration. The fibrin clot was integrated with the central iris, and the lens was not visible. Posaconazole therapy was initiated at an oral dose of 200 milligrams (mg) four times daily in combination with hourly topical ocular application of posaconazole suspension (10 mg/0.1 milliliter). During the first week of therapy, significant clearing of the corneal periphery was observed and the fibrin clot began to melt concentrically, with greater than 90% of the clot clearing after two weeks of treatment. At 16 months, the woman's vision was stable, with good color vision and full peripheral visual function and prognosis for rehabilitation of the eye was very good (Sponsel et al, 2002).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, no; pediatric, no
  EFFICACY: Adult, possibly effective
  DOCUMENTATION: Adult, poor
  

• 2. SUMMARY :

  
   - Posaconazole has been useful in the treatment of 
     disseminated phaeohyphomycosis caused by 
     Exophiala spinifera
  

• 3. ADULT :
  
  • a. Posaconazole was effective in the treatment of disseminated phaeohyphomycosis caused by Exophiala spinifera in one patient. A 41-year-old woman with a history of relapsing phaeohyphomycosis (responding partially to itraconazole and flucytosine) experienced increased mycosis severity when she became pregnant. Signs and symptoms during pregnancy and at delivery included skin and ganglionic lesions, adenopathies, knee osteomyelitis, visual disturbances, fever, and abnormal results of blood chemistry tests. Following premature delivery of the baby, oral posaconazole therapy (200 milligrams four times daily after meals) was initiated due to the refractory nature of her disease to all available antifungal agents. Within 13 months of beginning posaconazole therapy, clinical and mycologic cures were achieved for disseminated phaeohyphomycosis involving the bone and eye, as well as the lymphatic and cutaneous systems; and posaconazole was discontinued. However, posaconazole treatment (400 mg twice daily) was restarted approximately 11 months later due to a recurrence of mycosis caused by Exophiala spinifera. Treatment was planned for a duration of 24 months. Posaconazole was well tolerated and no adverse effects were observed in this patient throughout an exposure period of greater than two years (Negroni et al, 2004).

• 1. OVERVIEW :

  
  FDA APPROVAL: Adult, no; pediatric, no
  EFFICACY: Adult, possibly effective
  DOCUMENTATION: Adult, poor
  

• 2. SUMMARY :

  
  Posaconazole was used in the treatment of severe,
  disseminated zygomycosis in a heart-transplant
  recipient
  

• 3. ADULT :
  
  • a. A male diabetic patient who developed MUCORMYCOSIS (zygomycosis) of the skin and heart following organ transplantation was successfully treated with oral posaconazole therapy. The 56-year-old man underwent heart and kidney transplantation and developed zygomycosis at the site of the surgical wound following the operation. One week following surgery, the patient had not improved on antibiotic therapy and the fungal infection disseminated to the heart, with magnetic resonance imagery showing cardiomegaly and loculated pleural and pericardial effusions. The patient became unconscious, febrile, hemodynamically unstable, and exhibited increased blood glucose levels (250 milligrams/deciliter (mg/dL)), and abnormal increases in blood urea nitrogen (50 mg/dL) and serum creatinine levels (2.5 mg/dL). The man received approximately 6 weeks of amphotericin B therapy before oral treatment with posaconazole was initiated at a dose of 200 milligrams four times daily. Following one week of posaconazole therapy, the patient regained consciousness and no longer displayed altered neurological function. Serum creatine and blood urea nitrogen levels decreased, as did his blood glucose levels. The patient's fever resolved within 2 weeks of treatment and after 3 weeks of posaconazole therapy he was ambulatory and the surgical wound was almost entirely healed. The man was discharged by week 4 of treatment and continued posaconazole therapy at the same dose for a total of 23 weeks with no major adverse effects (Tobon et al, 2003).