Posaconazole

Uses

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.

For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals.

Posaconazole is also used to associated treatment for these conditions: Candidiasis, Coccidioidomycosis, Esophageal Candidiasis, Infections, Fungal, Invasive bronchopulmonary aspergillosis, Mucormycosis, Oropharyngeal Candidiasis, Prophylaxis of Aspergillus infection, Pulmonary cryptococcosis infection

How Posaconazole works

As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death.

Toxicity

During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.

Food Interaction

• Take with food. Posaconazole suspension can also be taken with a nutritional supplement drink or carbonated beverage if a full meal cannot be consumed.

[Moderate] ADJUST DOSING INTERVAL: Food significantly increases the absorption of posaconazole from the oral suspension but only modestly from the delayed-release tablet.

Following single-dose administration, posaconazole mean peak plasma concentration (Cmax) and systemic exposure (AUC) are approximately 2.5 to 3 times higher when the oral suspension is given with a nonfat meal or a nutritional supplement (14 grams of fat) than when given under fasting conditions, and approximately 3.5 to 4 times higher when given during or 20 minutes after a high-fat meal (50 grams of fat) than under fasting conditions.

Acidic beverages may also increase posaconazole absorption.

In 12 healthy volunteers, administration of a single 400 mg dose of posaconazole suspension with 12 ounces of ginger ale increased posaconazole Cmax by 92% and AUC by 70% compared to administration after fasting.

In contrast, the Cmax and AUC of posaconazole increased by just 16% and 51%, respectively, when posaconazole tablets were given as a single 300 mg dose to healthy volunteers after a high-fat meal relative to a fasted state.

GENERALLY AVOID Concomitant use of alcohol and posaconazole administered in the form of delayed-release oral suspension may lead to a faster release of posaconazole.

An in vitro dissolution study determined a potential for alcohol-induced dose-dumping with the delayed-release oral suspension of posaconazole.

MONITOR: In 5 study subjects, posaconazole Cmax decreased by 27% to 53% and AUC decreased by 33% to 51% when the oral suspension was administered via a nasogastric tube as opposed to orally.

MANAGEMENT: Posaconazole tablets should be taken with food, whereas posaconazole oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance bioavailability.

Patients who cannot eat a full meal should take the suspension with a liquid nutritional supplement or an acidic carbonated beverage such as ginger ale.

In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking another formulation of posaconazole, alternative antifungal therapy should be considered; otherwise, monitor patients closely for breakthrough fungal infections.

Patients receiving posaconazole via a nasogastric tube should also be closely monitored due to increased risk of treatment failure associated with lower plasma exposure.

Administration of alcohol with posaconazole from the delayed-release oral suspension formulation is not recommended.

Posaconazole Drug Interaction

Major: apixabanModerate: ciprofloxacin, levofloxacin, albuterol, pantoprazole, ondansetronMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprimUnknown: ibuprofen, amoxicillin / clavulanate, diphenhydramine, pancrelipase, meperidine, magnesium amino acids chelate, acetaminophen, dornase alfa, valacyclovir, cyanocobalamin, cholecalciferol

Posaconazole Disease Interaction

Major: hereditary fructose intoleranceModerate: QT prolongation, diarrhea/vomiting, electrolyte disturbances, hepatotoxicity, renal dysfunction

Volume of Distribution

• 1774 L

Elimination Route

Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.

Half Life

Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).

Clearance

• 32 L/hr
• 51 L/hr [Single-Dose Suspension Administration of 200 mg, fasted]
• 21 L/hr [Single-Dose Suspension Administration of 200 mg, nonfat meal]
• 14 L/hr [Single-Dose Suspension Administration of 200 mg, high fat meal]
• 91 L/hr [Single-Dose Suspension Administration of 400 mg, fasted]
• 43 L/hr [Single-Dose Suspension Administration of 400 mg with liquid nutritional supplement (14 g fat)]

Elimination Route

The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Innovators Monograph

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