indication

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.

pharmacology

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.

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.

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.

biotransformation

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

absorption

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).

route of elimination

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

drug interactions

Astemizole: Contraindicated co-administration

Bromazepam: Posaconazole may increase the serum concentration of bromazepam by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bromazepam if posaconazole is initiated, discontinued or dose changed.

Cimetidine: Significant decrease of posaconazole levels

Cisapride: Contraindicated co-administration

Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Concomitant use of conivaptan with strong CYP3A4 inhibitors (e.g., azole antifungals) is contraindicated.

Cyclosporine: Increased level of cyclosporine

Dantrolene: Posaconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if posaconazole is initiated, discontinued or dose changed.

Dihydroergotamine: Contraindicated co-administration

Ergotamine: Contraindicated co-administration

Fosphenytoin: Modifications of drug levels for both agents

Halofantrine: Contraindicated co-administration

Methysergide: Contraindicated co-administration

Phenytoin: Modifications of drug levels for both agents

Pimozide: Contraindicated co-administration

Quinidine: Contraindicated co-administration

Rifabutin: Modification of drug levels for both agents

Rivaroxaban: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Tacrolimus: The strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Posaconazole is initiated, discontinued or dose changed.

Tadalafil: Posaconzole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Posaconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Tamsulosin: Posaconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Posaconazole is initiated, discontinued, or dose changed.

Telithromycin: Posaconazole may increase the plasma concentration of Telithromycin. Consider alternate therapy or monitor therapeutic/adverse effects.

Temsirolimus: Posaconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Posaconazole is initiated, discontinued or dose changed.

Terfenadine: Contraindicated co-administration

Tiagabine: The strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Posaconazole is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may increase the serum concentration of Posaconazole. Posaconazole may increase the serum concentration of Tipranavir.

Tolterodine: Posaconazole may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Posaconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Posaconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Posaconazole is initiated, discontinued or dose changed.

Trimipramine: The strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Posaconazole is initiated, discontinued or dose changed.

Vardenafil: Posaconazole, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Venlafaxine: Posaconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Posaconazole is initiated, discontinued, or dose changed.

Verapamil: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Posaconazole is initiated, discontinued or dose changed.

Vinblastine: Posaconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Posaconazole is initiated, discontinued or dose changed.

Vincristine: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Posaconazole is initiated, discontinued or dose changed.

Vinorelbine: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Posaconazole is initiated, discontinued or dose changed.

Zolpidem: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if posaconazole is initiated, discontinued or dose changed.

Zonisamide: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if posaconazole is initiated, discontinued or dose changed.

Zopiclone: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if posaconazole is initiated, discontinued or dose changed.