Posiole Injection

Indications

• Invasive aspergillosis
• Fusariosis
• Chromoblastomycosis and mycetoma
• Coccidioidomycosis

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing information.

Adults: Refer to BNF for specific dosing guidelines. Doses may vary based on the indication and patient condition.

Mechanism of action

Posaconazole exerts its antifungal activity by inhibiting the cytochrome P-450 dependent enzyme, sterol 14-alpha-demethylase, which is crucial for the synthesis of ergosterol, a vital component of the fungal cell membrane. By binding to the heme cofactor of this enzyme, posaconazole disrupts ergosterol synthesis, leading to an accumulation of toxic sterol precursors and resulting in impaired cell growth and eventual cell death.

Pharmacodynamics

Structurally related to itraconazole, posaconazole's modifications enhance its potency and spectrum of antifungal activity. It can exhibit fungicidal or fungistatic effects depending on the concentration and the fungal strain. Its effectiveness against a wide array of fungi makes it a valuable option in the management of invasive fungal infections.

Pharmacokinetics

Posaconazole is available in oral and intravenous formulations. Its bioavailability is significantly affected by food intake; therefore, it is recommended to avoid taking the oral solution with food. Posaconazole is highly lipophilic, leading to extensive tissue distribution. It is metabolized primarily in the liver via CYP3A4, and its elimination half-life is approximately 35 hours, allowing for once-daily dosing in many cases. Caution is advised in patients with hepatic impairment due to the risk of hepatotoxicity.

Contra-indications

• History of congestive heart failure
• Severe hepatic disorders

Adverse effects

• Headache
• Nausea
• Vomiting
• Diarrhoea
• Fatigue
• Anorexia
• Pulmonary oedema
• Skin reactions
• Altered taste
• Dysphonia
• Hearing loss
• Tremor
• Hypersensitivity reactions
• Angioedema
• Severe cutaneous adverse reactions (SCARs)
• Pancreatitis
• Photosensitivity
• Hypertriglyceridaemia
• Peripheral neuropathy
• Thrombocytopenia
• Leucopenia
• Erectile dysfunction
• Urinary incontinence
• Increased risk of infection

Interactions

• Primidone - decreases concentration of posaconazole
• Phenobarbital - decreases concentration of posaconazole
• Antiarrhythmics - increases exposure to posaconazole
• Disopyramide - increases exposure to posaconazole
• Dronedarone - increases exposure to posaconazole
• Second-generation antipsychotics - increases exposure to posaconazole
• Lurasidone - increases exposure to posaconazole
• Statins - increases exposure to posaconazole
• Atorvastatin - increases exposure to posaconazole
• Efavirenz - decreases exposure to posaconazole

Precautions

• Caution in patients with renal impairment
• Caution with intravenous use in mild hepatic impairment
• Monitor for signs of liver disorder

Pregnancy

Manufacturer advises caution during pregnancy; potential benefit must outweigh risk.

Breast-feeding

Small amounts present in milk; manufacturer advises to avoid breastfeeding during treatment.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral solution (50 mg/5 ml)
• Capsules (100 mg)

Mechanism of action

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. Posaconazole is a novel lipophilic antifungal triazole that inhibits cytochrome P450-dependent 14-alpha demethylase in the biosynthetic pathway of ergosterol. Inhibition of this enzyme leads to an accumulation of toxic 14-alpha methylsterols and a depletion of ergosterol, resulting in a perturbation of the function of the fungal cell membrane and blockage of cell growth and division. ... ... The primary mechanism of action of the drug was inhibition of the parasite's sterol C-14 alpha demethylase. The in vitro activity of the novel triazole antifungal agent posaconazole was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.

Pharmacodynamics

Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action.