Posaconazole Enteric Tablets Instructions

Lactating women

Posaconazole is excreted into the milk of lactating rats. It is not known whether this product is excreted into human milk. Because of the potential for serious adverse reactions in nursing infants, the decision to discontinue nursing or discontinue drug therapy should be made considering the importance of the drug to the mother.

Fertility

Posaconazole at a maximum dose of 180 mg/kg (exposure level of 300 mg, 3.4 times the twice-daily dosing regimen based on steady-state plasma concentrations in healthy volunteer subjects) or 45 mg/kg (exposure level of 300 mg, 2.6 times the twice-daily dosing regimen) did not have any effect on fertility in male or female rats, respectively. There were no effects on fertility in male or female rats, respectively. There is no clinical experience evaluating the effects of posaconazole on human fertility.

[Pediatric Dosage].

The safety and efficacy of posaconazole oral suspension and posaconazole enteric-coated tablets have been demonstrated in the 13- to 17-year-old age group. Adequate and well-controlled adult studies provide evidence for the use of posaconazole in these populations. The safety and efficacy of posaconazole in pediatric patients under 13 years of age (from birth to 12 years) have not been established.

A total of 12 patients aged 13 to 17 years received a dose of posaconazole oral suspension 600 mg daily (200 mg three times daily) for the prevention of invasive fungal infections. The safety profile in these patients younger than 18 years of age was similar to that of adults. Based on pharmacokinetic data in 10 pediatric patients, the mean steady-state posaconazole concentrations (Cavg) were similar in these patients and adults (≥ 18 years of age). In a study involving another indication, a total of 136 patients aged 11 months to less than 18 years were treated with posaconazole oral suspension at a total daily dose of up to 18 mg/kg, divided into three daily doses, and approximately 50% of patients (rather than a predetermined 90% of patients) achieved a target steady-state posaconazole concentration (Cavg) exposure between 500 ng/mL and less than between 2500ng/mL.

[Geriatric Dosing

Thirty-eight of 230 patients (17%) treated with posaconazole enteric coated tablets were >65 years of age. The pharmacokinetics of posaconazole enteric-coated tablets were similar in younger and older subjects. No overall differences in safety were observed between older and younger patients, and therefore no adjustment of dosing in older patients is recommended.

Of the 605 patients randomized to posaconazole oral suspension in the prophylactic clinical trial, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with ≥800 mg daily posaconazole in another indication were ≥65 years of age. There was no overall difference in the safety of posaconazole between older and younger patients.

In younger and older (≥ 65< span style="font-family:Arial">years) subjects, the pharmacokinetics of posaconazole oral suspension were similar. In elderly patients, no age-based dose adjustment of this product is required.

There were no overall differences in pharmacokinetics and safety between older and younger subjects during clinical trials, but greater sensitivity in some older adults cannot be ruled out.

[Drug Interactions].

Posaconazole is primarily administered via UDP glucosylation for metabolism and is pglycoprotein (P-gp) substrate for pump-out action. Therefore, inhibitors or inducers of these clearance pathways can have an impact on posaconazole plasma concentrations. Unless the benefits to the patient outweigh the risks, posaconazole should generally be avoided with concomitant administration of drugs that may reduce posaconazole plasma concentrations. If such drugs must be administered, patients should be closely monitored for breakthrough fungal infections.

Posaconazole is alsoCYP3A4 a drug that can be used to treat fungal infections. /span>a potent inhibitor of CYP3A4. Thus posaconazole can increase plasma concentrations of drugs that are metabolized primarily by CYP3A4.

1, by < CYP3A4metabolized by immunosuppressants

Sirolimus: oral posaconazole administered in repeated doses in healthy subjects (daily2times oral suspension400 mgfor16days), sirolimus (2mgsingle dose) of CC sub>maxandAUCby an average of 6.7fold and 8.9fold. When starting posaconazole therapy in patients taking sirolimus, the dose of sirolimus should be reduced (e.g., to 1/10), and frequent monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be monitored prior to initiation of dosing, during concomitant dosing, and at the termination of posaconazole therapy, and sirolimus dose should be adjusted accordingly.

Tacrolimus: Posaconazole can cause tacrolimus (0.05 mg/kgsingle dose) of C_max< span style="font-family:Arial">andAUCvalues were significantly increased, respectively span>121%and358%358%. Reduce the dose of tacrolimus to approximately one-third of the initial dose at the start of posaconazole therapy. The tacrolimus troughs should be monitored frequently during and after discontinuation of posaconazole therapy and the tacrolimus dose should be adjusted accordingly.

Cyclosporine: after starting posaconazole therapy, posaconazole oral suspension200 mgdaily1times can result in elevated cyclosporine whole blood concentrations in heart transplant patients. It is recommended that the dose of cyclosporine be reduced to approximately three-quarters of the initial dose at the time posaconazole therapy is initiated. The trough values of cyclosporine whole blood concentrations should be monitored frequently during and after discontinuation of posaconazole therapy, and cyclosporine dose should be adjusted accordingly.

2,. span>CYP3A4substrate

Posaconazole withCYP3A4substrates such as pimozide and quinidine in combination can lead to elevated plasma concentrations of the above drugs, resulting inQTc< span style="font-family:Arial">interval prolongation and tip-twisting ventricular tachycardia. Therefore, posaconazole is contraindicated in combination with these drugs.

3, by < /span>CYP3A4metabolized byHMG-CoAreductase inhibitors (statins)

Orally administered posaconazole in repeated doses (daily1time oral suspension50,100,200 mg, continuous13day) of simvastatin (40 mgsingle dose)< span style="font-family:Times New Roman">C_maxandAUC increased on average by 7.4 respectively family:Arial”>to11.4fold andfold respectively. family:Times New Roman”>5.7to10.6fold. Increased plasma concentrations of HMG-CoAreductase inhibitors may accompany rhabdomyolysis. Prohibition of posaconazole with CYP3A4metabolism primarily via family:Times New Roman”>HMG-CoAreductase inhibitors are taken concurrently.

4, ergot Alkaloids
.

Most ergot alkaloids are CYP3A4substrates. Posaconazole causes elevated plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergot toxicity. Therefore, the combination of posaconazole and ergot alkaloids is prohibited.

5, by < CYP3A4metabolized by benzodiazepines

Posaconazole coadministered with midazolam results in elevated midazolam plasma concentrations of approximately5fold. Oral posaconazole repeated dose administration (2times daily oral suspension200 mg for7days) respectively, increasing intravenous administration of midazolam (0.4 mgsingle dose)C_maxandandAUCaverage1.3 times and4.6 times. 2times dailyPosaconazole Oral Suspension400 mg for7day, respectively, increasing midazolamC_maxandAUCof1.6 times and6.2fold. Posaconazole2doses were increased by oral midazolam (2mgorally as a single dose)C_max andAUCof2.2fold and4.54.5times. In addition, concomitant oral posaconazole (200 mgor or400 mgorally administered suspension) can result in a change in the mean terminal half-life of midazolam from approximately3-4hours to8-10hours. In contrast, elevated plasma concentrations of midazolam enhance and prolong the hypnotic and sedative effects.

Posaconazole is associated with other drugs that are effective through CYP3A4metabolized benzodiazepines (e.g., alprazolam, triazolam) can lead to elevated plasma concentrations of these benzodiazepines when coadministered. Treated patients must be monitored closely for the occurrence of excessive plasma concentrations of benzodiazepines metabolized via CYP3A4. adverse reactions, and benzodiazepine receptor antagonists must be available to reverse these reactions. Dose adjustment of benzodiazepines metabolized by CYP3A4is recommended during concomitant administration with posaconazole.

6, anti, anti span>HIVdrugs

BecauseHIV< span style="font-family:Arial">protease inhibitors as CYP3A4substrates. Posaconazole is expected to increase the plasma levels of these antiretroviral agents. In healthy subjects, repeated dose administration of oral posaconazole (daily2times oral suspensions =”font-family:Times New Roman”>400 mgconsecutively7< span style="font-family:Arial">days) respectively with an average increase of atazanavir (daily1 times300 mg, continuously7days) ofC_max =”font-family:Arial”>andAUC2.6times and3.7fold. In healthy subjects, when taking ritonavir (daily1times300 mgazanavir plus100 mg< span style="font-family:Arial">ritonavir for 7days) as an adjunctive regimen When oral posaconazole is repeatedly administered (2times dailyoral suspensions400 mg continuously7days) respectively, a smaller average increase in atazanavirC_maxandAUC1.5times and2.5fold. Frequent monitoring for adverse events associated with antiretroviral agents (CYP3A4enzyme-acting agents) is recommended during concomitant administration with posaconazole and toxicity.

Efavirenz: Efavirenz induces UDP-glucocerebrosidase and significantly reduces posaconazole plasma concentrations. 400 mgdaily1times may reduce posaconazoleC_maxandAUCof45%and50%. Avoiding efavirenz in combination with posaconazole is recommended unless the benefit outweighs the risk.

Ritonavir and atazanavir: Ritonavir and atazanavir are administered viaCYP3A4metabolism, and posaconazole causes elevated plasma concentrations of these drugs . Adverse reactions and toxicity should be monitored frequently during coadministration with posaconazole, and dose adjustments should be made for ritonavir and atazanavir.

Fosamprenavir: Combining fosamprenavir and posaconazole may result in lower posaconazole plasma concentrations. Close monitoring of breakthrough fungal infections is recommended if concomitant administration is required. Fosamprenavir (700 mgdaily2times a day for10consecutive family:Arial”>day) repeated dosing reduced posaconazole (day1day oral suspension daily >1time200 mg and the next day oral suspension daily2times200 mg, followed by continuous8days of oral suspension daily2times400 mg)C_maxandAUCof21%and23%.

7, rifabutin Ting

Rifabutin inducesUDP-glucocerebrosidase, rifabutin300 mg1times dailyreduces posaconazoleC_maxandAUCAUCof43%and49%. Rifabutin is also metabolized via CYP3A4. Therefore, the coadministration of rifabutin with posaconazole leads to rifabutinC_maxand AUC were elevated by 31%and72%. The combination of posaconazole with rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if a combination is required, close monitoring for breakthrough fungal infections and frequent monitoring for complete blood counts and adverse effects (e.g., uveitis, leukopenia) is recommended due to elevated rifabutin plasma concentrations.

8, phenytoin

Phenytoin inducesUDP-glucosidase, phenytoin200 mg1times dailyreduces posaconazole respectively family:Times New Roman”>C_maxandAUCof41%andand span>50%. Phenytoin is also metabolized via CYP3A4. Therefore, coadministration of phenytoin with posaconazole results in elevated phenytoin plasma concentrations. The combination of posaconazole with phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if coadministration is required, close monitoring of breakthrough fungal infections, frequent monitoring of phenytoin concentrations, and consideration of phenytoin dose reduction are recommended when coadministered with posaconazole.

9, gastric acid inhibitors/neutralizers

No clinically relevant effects on posaconazole pharmacokinetics have been observed when posaconazole enteric-coated tablets are used concomitantly with antacids, H2 receptor antagonists, and proton pump inhibitors. Concomitant use of posaconazole enteric tablets with antacids, H2 receptor antagonists, and proton pump inhibitors does not require adjustment of posaconazole enteric tablets dosing.

10, perphenazine

Most periwinkle alkaloids (e.g. periwinkle and periwinkle) areCYP3A4substrates. Serious adverse reactions have been associated with the combination of vincristine and azole antifungals, including posaconazole (see “Precautions”). Posaconazole can cause elevated plasma concentrations of Vincristine, which can lead to neurotoxicity and other serious adverse reactions. Therefore, treatment with azole antifungals, including posaconazole, may be reserved for patients on vincristine, including vincristine, when no other antimicrobial treatment options are available.

11, by CYP3A4metabolized by calcium channel blockers

Posaconazole may lead to a significant increase in calcium metabolism via CYP3A4increased plasma concentrations of metabolized calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity associated with calcium channel blockers is recommended during combination therapy. Dose reduction of calcium channel blockers may be required.

12. Digoxin

Elevated digoxin plasma concentrations have been reported in patients receiving digoxin in combination with posaconazole. Therefore, monitoring of plasma concentrations of digoxin is recommended during combination therapy.

13, gastrointestinal Power drugs

Concurrent administration of metoclopramide with posaconazole enteric-coated tablets does not affect the pharmacokinetics of posaconazole. No adjustment of posaconazole enteric-coated tablets dosing is required when administered concomitantly with metoclopramide.

14, Glipizide Pyrazine

A single 10-mg dose of glipizide had no clinically significant effect on the C_max and AUC of posaconazole. Although no dose adjustment of glipizide is required when posaconazole is coadministered with glipizide, monitoring of glucose concentrations is nevertheless recommended.

15. Zidovudine (AZT), lamivudine (3TC), and indinavir

Clinical studies have shown no clinically significant effects of zidovudine, lamivudine, or indinavir when taken concomitantly with posaconazole. Therefore, concomitant administration with these drugs does not require dose adjustment.

[Drug overdose].

There has been no experience with drug overdose with posaconazole enteric-coated tablets.

During the clinical trial, some patients were treated with the maximum dose of posaconazole oral suspension of 1600 mg daily, and these patients experienced adverse events that did not differ from the results observed at the lower dose. In addition, an unintentional overdose occurred in one patient who received 1200 mg twice daily for 3 days. The investigators found no drug-related adverse events.

Posaconazole was not cleared by hemodialysis.

[Clinical trial].

Study 5615 was a noncomparative multicenter study designed to evaluate the pharmacokinetic profile, safety, and tolerability of posaconazole enteric-coated tablets. The study population was similar to that of patients previously enrolled in the pivotal posaconazole oral suspension. Pharmacokinetic data and safety data from Study 5615 were bridged to existing data from the oral suspension (including efficacy data).

The subject population for Study 5615 included 1) patients with AML or MDS who had recently received chemotherapy and had developed or were expected to develop severe neutropenia, or 2) patients who had received HSCT and were receiving immunosuppressive therapy for the prevention or treatment of GVHD. Two different dosing groups were evaluated in this study: 200 mg twice daily on day 1, followed by 200 mg once daily (part IA); and 300 mg twice daily on day 1, followed by 300 mg once daily (parts IB and 2).

For all subjects in part 1 and a subgroup of subjects in part 2, serial PK samples were collected on day 1 and on day 8 when steady state was reached. In addition, for a larger population of subjects, sparse PK samples were collected before the next dose administration (C_min) on the days when steady state was reached. Based on the mean C_min concentration, the predicted mean concentration (C_avg) can be calculated for 186 subjects given 300 mg of the drug. PK analysis of patients with C_avg showed that 81% of patients receiving 300 mg of the drug once daily achieved steady-state predicted C_avg (500 -2500 ng/mL). 1 subject (<1 %) developed pC_avg below 500 ng/mL, and 19% developed pC_avg above 500 ng/mL. Nineteen percent of subjects developed pC_avg above 2500 ng/mL. The mean steady-state pC_avg achieved by subjects was 1970 ng/mL.

In Table 7 are shown the results of comparative exposure levels (C_avg) after administration of posaconazole enteric tablets and posaconazole oral suspension at therapeutic doses in patients as described in the quartile analysis. Exposure levels after tablet administration were generally higher than those after posaconazole oral suspension administration, but there was overlap.

Table 7: C_avg Quartile Analysis of Posaconazole Enteric Tablets and Oral Suspensions in Pivotal Patient Studies

The study enrolled 65 Chinese subjects with neutropenia after chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Subjects received posaconazole enteric-coated tablets 300 mg, administered twice daily on day 1 and then 300 mg once daily for a minimum of 8 days and a maximum of 28 days. The first 20 subjects enrolled were assigned to subgroup 1, and the next 45 subjects were assigned to subgroup 2. Subgroup 1 subjects underwent intensive PK sampling on day 1 and steady-state day 8, and all 65 subjects underwent several sparse PK samplings before the next dose to reach steady state.

Predicted C_avg (pC_avg) was calculated for 64 evaluable subjects based on mean C_min concentrations. All subjects had pC_avg above 500 ng/ml; 59/64 (92.2%), 4/64 (6.3%) and 1/64 (1.6%) subjects had pC_avg in the range of 500 – 2500 ng/mL, 2500 – 3750 ng/mL and > 3750 ng/mL ranges. The mean predicted C_avg when subjects reached steady state was 1770 ng/mL.

Summary of the Posaconazole Enteric Tablets China PK Study

Trial 111 was a randomized, open, single-dose, three-phase (A: 300 mg posaconazole enteric-coated tablets administered on an empty stomach; B: 300 mg posaconazole intravenous infusion solution administered on an empty stomach; C: 300 mg posaconazole enteric-coated tablets administered after a high-fat breakfast) crossover in 18 healthy Chinese adult male and female subjects. Design of the clinical trial. One of the main objectives was to evaluate the pharmacokinetic profile of posaconazole enteric-coated tablets administered as a single dose in the fasting state in healthy Chinese subjects. This study found that the PK exposure of posaconazole enteric-coated tablets administered in the fasting state was within the range of previous clinical studies. The T_max of posaconazole enteric-coated tablets after administration in the fasted state was 4 h and the half-life was 25.21 h. The geometric mean values of AUC_0-inf and C_max were 25,263 hr*ng/mL and 674.5 ng/mL, respectively.

Posaconazole Oral Suspension Clinical Study Summary

1. Posaconazole oral suspension prevents Aspergillus and Candida infections

Two randomized, controlled studies of posaconazole for the prevention of invasive fungal infections (IFIs) in patients at increased risk due to severe immune system deficiency were conducted.

The first study (Oral Suspension Study 1) was a randomized, double-blind clinical trial comparing posaconazole oral suspension (200 mg 3 times daily) with fluconazole capsules (400 mg once daily) for the prevention of invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients presenting with graft-versus-host disease (GVHD). Effectiveness of prophylaxis was assessed using a composite endpoint including proven/very suspicious invasive fungal infection, death, or use of systemic antifungal therapy (patients may meet more than 1 criterion). This trial evaluated all patients 7 days after the end of study treatment and 16 weeks after randomization to the group. The mean duration of treatment was similar between the 2 treatment groups (80 and 77 days in the posaconazole and fluconazole treatment groups, respectively). The results of the oral suspension study 1 are shown in Table 8.

Table 8: Results of blinded clinical study 1 on oral suspension for the prevention of invasive fungal infections in all patients undergoing randomized grouping for hematopoietic stem cell transplantation (HSCT) and graft-versus-host disease (GVHD)

Study 2 (Oral Mix Study 2) is a study in neutropenic patients receiving cytotoxic chemotherapy for acute myeloid leukemia or myelodysplastic syndrome. A randomized, open study comparing posaconazole oral suspension (200 mg three times daily), fluconazole suspension (400 mg once daily), or itraconazole oral solution (200 mg twice daily) for the prevention of invasive fungal infections in patients with neutropenia receiving cytotoxic chemotherapy for acute myeloid leukemia or myelodysplastic syndrome. Similar to the oral suspension study1, prophylactic efficacy was assessed using a composite endpoint that included either confirmed/suspected invasive fungal infection, death, or the use of systemic antifungal therapy (patients may meet more than 1 criterion). This trial evaluated patients 7 days after the end of study treatment and 100 days after randomization to the group. The mean duration of treatment was similar between the 2 treatment groups (29 and 25 days in the posaconazole and fluconazole or itraconazole treatment groups, respectively). The results of Study 2 are shown in Table 9.

Table 9: Results of open clinical study 2 on oral suspensions for the prevention of invasive fungal infections in all patients with malignant hematologic disease and long-term neutropenia who received randomized subgroups

In summary, 2 prophylactic clinical studies of oral suspensions were conducted. As shown in the table (Tables 8 and 9), clinical failure was used as a composite end point, including breakthrough invasive fungal infection, death, and use of systemic antifungal therapy. In the oral mix study1 (Table 8), posaconazole (33%) had a similar rate of clinical failure to fluconazole (37%) (95% confidence interval for the posaconazole-control drug difference -11.5% to 3.7%). In contrast, in Oral Mix Study 2 (Table 9), the clinical failure rate was lower in patients treated with posaconazole (27%) than in those treated with fluconazole or itraconazole (42%) (95% confidence interval for the posaconazole-control drug difference -22.9% to -7.8%).

In the 2 treatment groups of the oral mix study 1, all-cause mortality at week 16 was similar [posaconazole 58/301 (19%) versus fluconazole 59/299 (20%)]; in the oral mix study 2, patients in the posaconazole-treated group had a lower all-cause mortality was lower than in the fluconazole/itraconazole-treated group [posaconazole 44/304 (14%) versus fluconazole/itraconazole 64/298 (21%)]. 2 studies demonstrated a lower incidence of breakthrough infections due to Aspergillus in patients receiving posaconazole prophylaxis than in patients receiving fluconazole or itraconazole treatment.

2. Posaconazole Oral Suspension for Oropharyngeal Candidiasis (OPC)

The Posaconazole Oral Suspension Study3 is a randomized, controlled, evaluator-blinded study in HIV-infected patients presenting with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (posaconazole and fluconazole were administered as indicated below: 100 mg twice daily for 1 day, followed by 100 mg once daily for 13 days).

Clinical and fungal outcomes were evaluated after 14 days of treatment and at week 4 after the end of treatment. Patients who received at least 1 study drug and had positive oral swab cultures for Candida at baseline were included in the analysis (Table 10). The majority of subjects had a baseline phase pathogen of Candida albicans.

The rates of clinical success (complete or partial remission of all ulcers and/or plaques and symptoms) at day 14 and clinical relapse (recurrence of signs or symptoms after initial cure or improvement) at 4 weeks after the end of treatment were similar in the 2 treatment groups (Table 10).

The rates of fungal eradication (absence of colony-forming units in quantitative cultures on day 14 at the end of treatment) and fungal relapse (4 weeks after the end of treatment) were also similar in the 2 treatment groups (see Table 10).

Table 10: Clinical success, fungal eradication, and recurrence rates of posaconazole oral suspension in oropharyngeal candidiasis

In the 2 treatment The fungal response rates were also similar in the groups (posaconazole 68.0%, fluconazole 68.1%), where the success criterion was a post-treatment quantitative culture with ≤ 20 colony-forming units (CFU/ml). The clinical significance of this result is unknown.

3. Posaconazole oral suspension for fluconazole- or itraconazole-refractory oropharyngeal candidiasis

The Posaconazole Oral Suspension Study4 is an uncontrolled study of Posaconazole oral suspension in HIV-infected patients presenting with fluconazole- or itraconazole-refractory oropharyngeal candidiasis. Oropharyngeal candidiasis was considered refractory if no improvement or exacerbation of oropharyngeal candidiasis was obtained after a standard course of fluconazole ≥100 mg daily for at least 10 consecutive days or itraconazole 200 mg daily for at least 10 consecutive days, and if fluconazole or itraconazole treatment was not discontinued more than 14 days before posaconazole treatment. Of the 199 subjects enrolled in this study, 89 met the strict criteria for refractory infection.

Forty-five subjects who developed refractory oropharyngeal candidiasis received posaconazole oral suspension 400 mg twice daily for 3 days, followed by 400 mg once daily for 25 days with an option to continue treatment for a 3-month maintenance period. After dose adjustment, an additional 44 subjects received posaconazole 400 mg twice daily for 28 days. The effectiveness of posaconazole was evaluated by clinical success (cure or improvement) rate after a 4-week treatment period. The clinical success rate was 74.2% (66/89). Clinical success rates were similar for the initial and modified dosing regimens (73.3% and 75.0%, respectively).

[Pharmacology and Toxicology

Pharmacological effects

Mechanism of action.

Posaconazole, a triazole antifungal, is a potent inhibitor of lanolin 14-demethylase, the catalytic enzyme for a key step in ergosterol biosynthesis. Posaconazole produces its antifungal effect by inhibiting lanolin 14-demethylase on the fungal cell membrane.

Microbiology.

In vitro tests and clinical infection studies have shown that posaconazole has antibacterial activity against the following microorganisms: Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus oryzae, Aspergillus niger, Aspergillus pyogenes, Aspergillus ochraceus), Candida spp. (Candida albicans, Candida smoothus, Candida klebsiella, Candida subsmoothus), Cryptococcus neoformans, Clostridium vulgaris, Peptostreptococcus, Histoplasma intercalatum, Clostridium spp. Pseudoalicium bovis, Streptomyces spp, Ectoplasma spp, Fusarium spp, Dictyostelium spp, Trichoderma spp, Trichoderma spp and Rhizopus spp.

In vitro tests have shown that posaconazole also has antibacterial activity against the following yeasts and molds: Candida dublin, Candida saprophyticus, Candida quinquefaciens, Candida portugal, Candida lactis, Candida rugosa, Candida tropicalis, Candida salivarius, Candida ordinarius, Candida decidua, Candida norvegicans, Candida pseudotropicalis, Cryptococcus laurenti, Candida maxicruvii, Saccharomyces cerevisiae, Saccharomyces cerevisiae, Saccharomyces cerevisiae, Saccharomyces cerevisiae, Saccharomyces cerevisiae. Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon polysporon, Trichosporon fumigatus, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp, Trichosporon spp. However, there are no clinical trial studies on the safety and efficacy of posaconazole in the treatment of clinical infections caused by these microorganisms.

Posaconazole has broad-spectrum antifungal activity against yeasts and molds that do not respond to treatment with certain azoles or are resistant to other azoles.

style=”margin-left: 38pt”>
• Candida spp. (including isolates of Candida albicans resistant to fluconazole, voriconazole, and itraconazole (including Candida albicans isolates that are resistant to fluconazole, voriconazole, and itraconazole, Candida klebsiella and Candida smoothus that are not themselves susceptible to fluconazole treatment, and Candida portugal that is not itself susceptible to amphotericin B treatment)

style=”margin-left: 38pt”>
• Aspergillus spp. (including those sensitive to fluconazole, voriconazole, >itraconazole and amphotericin B resistant isolates)

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• Microorganisms previously identified as insensitive to azoles, such as jointed bacteria (e.g., Plasmodium spp., Trichoderma spp., Rhizopus spp. and Rhizopus spp.)

In vitro, posaconazole has bactericidal activity against the following genera.

style=”margin-left: 38pt”>
• Trichoderma spp.

style=”margin-left: 38pt”>
• Biphasic fungi (Bacillus dermatitidis, Histoplasma capsulatum, Penicillium marneffei, Coccidioides crassus)
• Some Candida spp.

Posaconazole has shown antibacterial activity against a wide range of fungal infections caused by mycobacteria or yeasts in animal infection models. However, no consistent correlation was obtained between minimum inhibitory concentration values and effectiveness.

Before treatment, fungal culture specimens and other relevant laboratory studies (including histopathology) should be obtained to isolate and identify the causative microorganism. Treatment may be administered until fungal culture and other laboratory results are reported. However, once these results are available, antifungal treatment regimens should be adjusted accordingly.

Drug resistance.

In the laboratory, no posaconazole-resistant strains of Candida albicans were identified; the frequency of spontaneous mutations in experimental Aspergillus fumigatus with reduced susceptibility to posaconazole increased to 1×10^-8 to 1×10^-9. Clinically meaningful reductions in susceptibility to posaconazole by Candida albicans and Aspergillus fumigatus isolates are rare. In those rare cases of reduced susceptibility, no significant association was found between reduced susceptibility and clinical treatment failure. Posaconazole has been successful in the treatment of patients with microbial infections resistant to other azoles; also, in vitro posaconazole is active against Aspergillus and Candida strains resistant to other azoles and/or amphotericin B. The folding point for fungal therapy with posaconazole has not been established.

Combination therapy with antifungal drugs:

Posaconazole co-administration with amphotericin B or caspofungin was tested in vitro and in vivo, and no drug antagonism was seen, and in some cases additive drug effects were observed. The clinical significance of these results has not been determined.

Toxicological studies

Genotoxicity.

Posaconazole Ames test, human peripheral blood lymphocyte chromosome aberration test, Chinese hamster ovary cell chromosome aberration test, and mouse bone marrow micronucleus test results were negative.

Reproductive toxicity.

No effect on fertility was seen with posaconazole in male rats given a maximum dose of 180 mg/kg (exposure 1.7 times the oral suspension 400 mg twice daily dosing regimen at steady-state plasma concentrations in healthy volunteers) or in female rats given 45 mg/kg (exposure 2.2 times the oral suspension 400 mg twice daily dosing regimen).

In rats, posaconazole doses ≥ 27 mg/kg (≥ 1.4 times the steady-state plasma drug concentration of the oral suspension 400 mg twice daily dosing regimen in healthy subjects) resulted in skeletal deformities (cranial deformities and rib deficiencies). In rats, no skeletal deformities were observed at a dose (no effect dose) of 9 mg/kg (0.7 times the exposure of the oral suspension 400 mg twice daily dosing regimen). In rabbits, no deformities were observed at the maximum dose of 80 mg/kg. In rabbits, the no-effect dose was 20 mg/kg, while higher doses of 40 and 80 mg/kg resulted in increased embryonic uptake, with these doses producing exposure levels 2.9 or 5.2 times higher than the 400 mg twice daily dosing regimen, respectively. In rabbits, reduced body weight gain and reduced litter size were observed in females at the 80 mg/kg dose.

Reproductive, perinatal, and postnatal developmental studies were conducted in rats. Posaconazole caused skeletal abnormalities and malformations, obstructed labor, prolonged gestation, reduced mean litter size, and reduced postnatal viability when exposure was below the human therapeutic dose. In rabbit trials, posaconazole produced embryotoxicity at exposures above therapeutic doses. As with other azole antifungals, these reproductive effects were associated with administration affecting steroid hormone production.

Carcinogenicity.

No drug-associated tumors were observed in a 2-year carcinogenicity trial in rats or mice given higher than clinical doses of posaconazole. In a 2-year carcinogenicity trial in rats given posaconazole orally at a maximum dose of 20 mg/kg (females) or 30 mg/kg (males), these doses produced exposures that were 3.9 or 3.5 times higher, respectively, based on steady-state AUC in healthy volunteers consuming a high-fat diet (oral suspension 400 mg twice daily regimen). In the mouse test, the maximum dose administered orally was 60 mg/kg per day, and the exposure was 4.8 times that of the oral suspension 400 mg twice daily regimen.

Other.

As with other azole antifungals, posaconazole was found to have an inhibitory effect on steroid hormone synthesis in repeated dosing toxicity tests. Adrenal suppression was found in rat and canine toxicity tests at exposures at or above human therapeutic doses.

At dosing≥ 3months in a canine toxicity test, neuronal phospholipidosis was observed when the systemic exposure was less than the human therapeutic dose exposure. These changes were not observed in a monkey toxicity trial administered for 1year. In a neurotoxicity test in dogs and monkeys over a period of 12months, when systemic exposure was greater than human therapeutic dose exposure, no effects were observed on central or peripheral nervous system effects.

in rats over a period of2. span>year trial, pulmonary phospholipidosis leading to alveolar dilatation and obstruction could be observed. These results do not necessarily represent the potential for functional alterations in humans.

In safety pharmacology trials with repeated dosing in monkeys, when the maximum plasma concentration was the plasma concentration of the human therapeutic dose8.5fold, no effects on ECG were observed, including QTandQTc Interval. In a repeated administration safety pharmacology test in rats, when systemic exposure was 2.1fold of the human therapeutic dose exposure, echocardiographic cardiogram did not suggest cardiac decompensation. In rats and monkeys, when systemic exposure was 2.1fold and fold of the human therapeutic dose exposure, respectively style=”font-family:Times New Roman”>8.5fold, elevated systolic and arterial blood pressures were observed (29 mmHg).

[Pharmacokinetics].

Posaconazole is an azole antifungal drug.

Dose-effect relationships: a wide range of posaconazole plasma exposure levels in clinical studies in neutropenic patients receiving cytotoxic chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) or in hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). Pharmacokinetic-pharmacodynamic analysis of patient data showed a significant correlation between mean posaconazole concentrations (C_avg) and prophylactic effectiveness (Table 11). Lower Cav may be associated with an increased risk of treatment failure, i.e., discontinuation of therapy, use of empiric systemic antifungal therapy (SAF), or development of breakthrough invasive fungal infections.

Table 11: In Analysis of Posaconazole Oral Suspension Exposure in Prevention Clinical Trials (C_avg)

General Pharmacokinetic Profile

The pharmacokinetics of posaconazole enteric-coated tablets after single and multiple doses up to 300 mg showed proportional to the dose administered. The mean pharmacokinetic parameters of posaconazole at steady state after administration of 300 mg twice daily (BID) on day 1 and once daily (QD) thereafter in healthy volunteers, neutropenic patients receiving cytotoxic chemotherapy for acute myeloid leukemia or myelodysplastic syndrome, or hematopoietic stem cell transplant recipients with graft-versus-host disease are shown in < strong>Table 12.

Table 12: Arithmetic mean (%CV) of steady-state pharmacokinetic parameters after administration of posaconazole enteric-coated tablets (300 mg)* in healthy volunteersand patients

:Oral administration in healthy volunteers of The medianT_max of absorption when posaconazole enteric-coated tablets are given orally is 4 to 5 h. Steady-state plasma concentrations are achieved by day 6 at a 300 mg dose (once daily, loading dose twice daily on day 1). The absolute bioavailability of oral enteric tablets was approximately 54% in the fasting situation. The C_max and AUC of posaconazole were elevated by 16% and 51%, respectively, when posaconazole enteric tablets were administered concomitantly with a high-fat diet compared with the fasting situation (see Table 13). To enhance posaconazole absorption and optimize plasma concentrations, posaconazole enteric-coated tablets should be taken with food.

Table 13: Statistical comparison of the plasma pharmacokinetics of single oral administration of 300 mg posaconazole enteric-coated tablets in healthy subjects under fasting and feeding