Posaconazole is a broad-spectrum, second generation, triazole compound with antifungal activity. Posaconazole strongly inhibits 14-alpha-demethylase, a cytochrome P450-dependent enzyme. Inhibition of 14-alpha-demethylase prevents the conversion of lanosterol to ergosterol, an important component of the fungal cell wall. Inhibition of ergosterol synthesis changes the fungal cell membrane composition and integrity, alters membrane permeability and eventually leads to fungal cell lysis. Compared to other azole antifungals, posaconazole is a significantly more potent inhibitor of sterol 14-alpha-demethylase.
Posaconazole is a potent triazole antifungal agent used in the prevention of invasive fungal infections due to aspergillosis and candida in high-risk patients. Posaconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a suspected but rare cause of clinically apparent acute drug-induced liver injury.
Mechanism of Action of Posaconazole
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 the accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death. It is a drug derived from itraconazole through the replacement of the chlorine substituents with fluorine 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 fungicidal or fungistatic in action.
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
Indications of Posaconazole
- Oropharyngeal candidiasis
- Aspergillosis, Invasive
- Oral Thrush
- Esophageal Candidiasis
- Infections, Fungal
- Invasive bronchopulmonary aspergillosis
- Oropharyngeal Candidiasis
- Prophylaxis of Aspergillus infection
- Prophylaxis of Candida Infections
- Pulmonary cryptococcosis infection
Contraindications of Posaconazole
- Have known hypersensitivity to other azole medicines such as posaconazole;
- Are taking terfenadine, if 400 mg per day multidose of fluconazole is administered;
- Concomitant administration of itraconazole and quinidine, especially when posaconazole is administered in high dosages;
- Take SSRIs such as fluoxetine or sertraline.
Dosage of Posaconazole
- 40mg/mL (105mL)
tablet, delayed release
- 18mg/mL (300mg/vial)
Dosages are following forms
- For prevention of fungal infections: the recommended dose is 200 mg (5 mL) three times a day of the oral suspension. Duration of therapy depends on the speed of recovery of certain white blood cells (your neutrophil count) and how weak your immune system is (immunosuppression).
- For treating oropharyngeal candidiasis: the recommended dose is to start with 100 mg (2.5 mL) twice a day of the oral suspension or 300 mg of the injection on the first day, then 100 mg (2.5 mL) of the oral suspension or 300 mg of the injection once a day for 13 days.
- For treating oropharyngeal candidiasis that is not cured by itraconazole or fluconazole: the recommended dose is 400 mg (10 mL) twice a day of the oral suspension. Duration of therapy should be based on the severity of the patient’s underlying disease and response to this medication.
In injection form
|Indication||Dose and Duration of Therapy|
|Prophylaxis of invasive Aspergillus and Candida infections||Loading dose:
300 mg Noxafil injection intravenously twice a day on the first day.
300 mg Noxafil injection intravenously once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.
Delay release tablet
|Indication||Dose and Duration of Therapy|
|Prophylaxis of invasive Aspergillus and Candida infections||Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.|
|Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.|
|Indication||Dose and Duration of Therapy|
|Prophylaxis of invasive Aspergillus and Candida infections||200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.|
|Oropharyngeal Candidiasis||Loading dose: 100 mg (2.5 mL) twice a day on the first day.|
|Maintenance dose: 100 mg (2.5 mL) once a day for 13 days.|
|Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole||400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response.|
Side Effects of Posaconazole
- Abdominal or stomach pain
- feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
- sudden tingling or coldness in an arm or leg
- liver problems,
- stomach pain,
- Burning, itching, stinging, redness, or other sign of irritation at the application site ,rash
- increased intracranial pressure,
- meningeal signs,
- reversible hair loss or thinning, and
- chills or fever
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in the chest
- discomfort in arms, shoulders, neck or upper back
- excessive sweating
- sudden slow or difficult speech
- sudden drowsiness or need to sleep
- fast breathing
- sharp pain when taking a deep breath
- fast or slow heartbeat
- coughing up blood
- rust colored urine
- decreased amount of urine
- change in vision
- chest pain or tightness
- a cough
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- extra heartbeats
- a headache
- mood or mental changes
- muscle pain or cramps
- muscle spasm or jerking of all extremities
Drug Interactions of Posaconazole
Do not take posaconazole if you are taking any of the following medicines
- sirolimus, pimozide; quinidine; certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)
- ergot alkaloids (ergotamine, dihydroergotamine)
Also, you should tell your healthcare provider if you:
- are taking certain medicines that lower your immune systems like cyclosporine or tacrolimus
- are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole.
- are taking midazolam, a hypnotic and sedative medicine
Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines.
FDA Pregnancy category C.
There are no adequate and well-controlled studies in pregnant women. Noxafil should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Posaconazole is excreted in the milk of lactating rats. It is not known whether Noxafil is excreted in human milk. Because of the potential for serious adverse reactions from Noxafil in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.