Posaconazole

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Contents

[edit] BRAND NAMES

  • Noxafil
  • Posanol

[edit] STRUCTURE

Posaconazole.jpg

[edit] MECHANISM OF ACTION

Posaconazole is a triazole antifungal. It inhibits lanosterol 14α-demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol.

Ergosterol is an essential component of the fungal cell membrane. The inhibition of its synthesis results in accumulation of toxic 14α-methylated sterols and the production of a defective cell membrane with altered permeability and leakage of cellular contents.

Unlike, Voriconazole that causes reversible visual disturbances immediately after usage, Posaconazole doesn’t show this problem.

Posaconazole crosses the BBB and is actually more similar to Voriconazole than the other azoles. It is metabolized and used for invasive aspergillosis.

[edit] INDICATIONS

  • Injection, delayed-release tablets, and oral suspension are indicated for Prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

Oral suspension

  • Oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

[edit] DOSAGE

Indication Dose and Duration of Therapy
Prophylaxis of 
invasive 
Aspergillus and 
Candida 
infections 

Injection*: 
Loading dose: 300 mg Posaconazole injection 
intravenously twice a day on the first day. 
Maintenance dose: 300 mg 'Posaconazole 'injection 
intravenously once a day thereafter. Duration of 
therapy is based on recovery from neutropenia 
or immunosuppression.
Delayed-Release Tablets † :
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. 
Oral Suspension‡ : 200 mg (5 mL) three times 
a day. Duration of therapy is based on recovery 
from neutropenia or immunosuppression. 
Oropharyngeal 
Candidiasis 
(OPC)
Oral Suspension‡ : 
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.

OPC Refractory 
(rOPC) to 
Itraconazole 
and/or 
Fluconazole
Oral Suspension‡ : 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient’s underlying disease and 
clinical response. 


*Posaconazole injection must be administered through an in-line filter. 
Administer by intravenous infusion over approximately 90 minutes via 
a central venous line. Never give Noxafil injection as an intravenous 
bolus injection. 
† Posaconazole  delayed-release tablets should be taken with food.
‡ Posaconazole  oral suspension should be taken with a full meal.

[edit] CONTRAINDICATIONS

  • Do not administer to persons with known hypersensitivity to posaconazole or other azole antifungal agents.
  • Do not coadminister posaconazole with the following drugs; posaconazole increases concentrations of:
    • Sirolimus: Concomitant administration of Posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity
    • CYP3A4 substrates that prolong the QT interval (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes
    • HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin): is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis
    • Ergot alkaloids: Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism

[edit] WARNINGS AND PRECAUTIONS

  • Calcineurin Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently.
  • Arrhythmias and QTc Prolongation: Posaconazole has been shown to prolong the QTc interval and cause cases of torsades de pointes. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4 (See contraindications). Correct K+, Mg++, and Ca++ before starting Posaconazole.
  • Hepatic Toxicity: Elevations in Liver function tests (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate

aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor Liver function tests during treatment.

  • Posaconazole injection should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Posaconazole injection.
  • Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available.

[edit] INTERACTIONS

Interaction Drug Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole* 
Avoid coadministration unless 
the benefit outweighs the risks
Other drugs metabolized by CYP3A4 
Consider dosage adjustment 
and monitor for adverse effects 
and toxicity
Digoxin 
Monitor digoxin plasma 
concentrations
Fosamprenavir, metoclopramide*
Monitor for breakthrough fungal 
infections
*The drug interactions with esomeprazole and metoclopramide do not apply to posaconazole tablets. 

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category C: (US): Based on animal data, may cause fetal harm.
  • Nursing Mothers: Discontinue drug or nursing, taking in to consideration the importance of drug to the mother.

[edit] SIDE EFFECTS

Common treatment-emergent adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia.

[edit] RELATED LINKS

Azoles mechanism of action

[edit] BIBLIOGRAPHY

[edit] REFERENCES

Antifungals
Ergosterol target : Cell membrane target Azoles (lanosterol 14 alpha-demethylase inhibitors) : Ergosterol inhibitors Imidazoles Topical: Bifonazole   Clotrimazole   Econazole   Fenticonazole   Ketoconazole   Isoconazole   Miconazole   Sertaconazole   Tioconazole
Triazoles Topical: Fluconazole   Terconazole
Systemic: Fluconazole   Itraconazole   Posaconazole   Voriconazole
Polyene antimycotics (ergosterol binding; they form pores in the membrane) Topical: Nystatin
Systemic: Amphotericin B
Allylamines (squalene epoxidase inhibitors) : Ergosterol inhibitors Topical: Amorolfine   Naftifine   Terbinafine
Systemic: Terbinafine
Echinocandins (β-glucan synthase inhibitors) : Cell wall target Anidulafungin   Caspofungin   Micafungin
Pyrimidine analogues / Thymidylate synthase inhibitors : Nucleic acid inhibitors Flucytosine
Mitotic inhibitors Griseofulvin
Others Ciclopirox