Abstract
Background. Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed.
Methods. A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for ⩾6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies.
Results. Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for <6 months and ⩾6 months.
Conclusions. Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.
Posaconazole (SCH56592) is an orally administered, extended-spectrum triazole antifungal agent. Activity of posaconazole against the most common fungal pathogens, as well as emerging, hard-to-treat, and endemic infections, has been demonstrated in in vitro studies and clinical trials [1–9]. The need for new treatment options for invasive fungal infections (IFIs) is indicated by increasing rates of opportunistic fungal pathogens in hospitalized patients [10] and reports of toxicities and emerging resistance to existing antifungal therapies [11, 12], suggesting that posaconazole will be an important treatment option for many patients [13].
Initial clinical studies indicated that oral posaconazole was well tolerated and associated with minimal cardiac and hepatic effects in healthy volunteers [14, 15]. In addition, posaconazole may be associated with a low potential for drug interactions caused by inhibitory activity against a narrow spectrum of cytochrome P450 (CYP) isozymes. Posaconazole is a potential inhibitor of CYP 3A4 only and is not significantly metabolized by any CYP isozyme [16, 17]. Favorable safety and tolerability results have also been presented in patients with IFIs [7, 18–20], including patients >65 years of age [21] and patients with chronic renal disease [22].
This article presents integrated safety data from a pooled set of patients (n = 428) who had febrile neutropenia (66 patients) or refractory IFIs (362 patients) in 2 phase II/III clinical trials of posaconazole. A significant proportion of these patients (108 patients; 25%) received posaconazole for ⩾6 months. Because few data on long-term safety of newer antifungal agents are available, safety data were analyzed separately for patients who received posaconazole treatment for <6 months and for those who received therapy for ⩾6 months.
Methods
Patient population and treatment. Analyses of safety were performed for a set of 428 patients who received posaconazole treatment in 2 phase II/III open-label studies. One trial was a pharmacokinetic dose—finding study, in which 98 patients with IFIs (32 patients) or febrile neutropenia (66 patients) were randomized to treatment with posaconazole (either 400 mg twice per day, 600 mg twice per day, or 800 mg once per day) for a maximum period of 6 months. The second study was a pivotal, phase III, nonrandomized trial, in which 330 patients with refractory IFIs were treated with 800 mg of posaconazole per day. The overall population of 428 patients included 397 patients who were assigned to receive 800 mg per day and 31 patients who were assigned to receive 1200 mg per day after an initial dose of 1600 mg per day for 2 days. Posaconazole was administered as an oral suspension in divided doses. Duration of therapy was based on the severity of underlying disease, the extent of recovery from immunosuppression, and the degree of clinical response for each patient.
Safety data were analyzed to compare 2 groups. The first group consisted of 319 patients who received all doses of posaconazole for <6 months. The second group consisted of 109 patients who received all doses of posaconazole treatment for ⩾6 months. Rates of follow-up monitoring and laboratory tests were the same in the short-term and long-term groups throughout the studies.
Adverse events. Treatment-emergent, treatment-related adverse events were defined as any physical or clinical change or disease experienced by the patient at any time during the study, including onset of new illness and exacerbation of preexisting conditions, which were defined as possibly or probably related to posaconazole treatment by the investigator or as events for which no relationship was specified. Serious adverse events were defined as those that were fatal, were life-threatening, were disabling, required hospitalization, or were considered medically significant by the investigator.
Electrocardiogram and laboratory data. In the pharmacokinetic dose—finding study, findings from electrocardiograms were recorded at baseline, at 10 h or 24 h after the first dose, and monthly thereafter or as clinically indicated. Hematologic testing and serum chemistry studies were performed weekly for 12 weeks and then performed monthly throughout the study or as clinically indicated. In the phase III trial, findings from electrocardiograms were recorded at baseline, at week 4 and as clinically indicated thereafter. Results of hematologic tests and serum chemistry studies were recorded at every visit (at weeks 2 and 4 and then monthly thereafter or as clinically indicated). Hematologic test and blood chemistry results were classified using Common Toxicity Criteria (CTC) grading, version 2.0 (National Cancer Institute) [23]. Potentially clinically significant shifts in these parameters were defined as shifts from CTC grade 0, 1, or 2 at baseline to grade 3 or 4 as the worst value that occurred at any time during treatment.
Results
Baseline demographic and disease characteristics. Characteristics of the overall population of patients with refractory IFIs who received all doses of posaconazole (n = 428) are shown in table 1. As expected for patients with IFIs, most were severely immunocompromised. Patients who received treatment with posaconazole for <6 months and for ⩾6 months had similar baseline demographic and disease characteristics.
Baseline demographic characteristics and disease characteristics of patients with refractory invasive fungal infections who received posaconazole.
Course of posaconazole treatment. The mean duration of posaconazole treatment among the overall population was 115 days (range, 1–609 days), with a median duration of 54 days. The actual exposure to treatment (treatment duration minus any missed doses or gaps in treatment) was very similar (mean duration of exposure to treatment, 113 days), suggesting a high level of compliance with the treatment regimen. A total of 109 patients received posaconazole for ⩾6 months, including 27 (25%) who received treatment for ⩾12 months. The maximum duration of treatment was 609 days (∼20 months).
Treatment-related adverse events and discontinuation due to adverse events. Among the overall population of patients, 164 (38%) of 428 reported adverse events were judged to be possibly or probably related to posaconazole treatment. In the dose-finding study, patients who received 400 mg of posaconazole twice a day, which was the regimen involving the greatest exposure to drug, reported more treatment-related adverse events than those who received 600 mg of posaconazole twice a day or 800 mg once a day (11 [31%] of 31, 6 [19%] of 31, and 7 [22%] of 32 patients, respectively), but the differences were not statistically significant. The most common treatment-related adverse events were gastrointestinal in nature (e.g., nausea, vomiting, diarrhea, and abdominal pain) (table 2).
Treatment-related adverse events reported in ⩾2% of patients with refractory invasive fungal infections who were assigned to receive posaconazole.
Treatment-related adverse events that led to discontinuation of therapy, discontinuation of the study, or death were reported in 25 (6%) of 428 patients. Table 3 compares these events in patients who received posaconazole for <6 months and those who received posaconazole for ⩾6 months. Overall, more patients (8 [32%] of 25) discontinued treatment because of treatment-related gastrointestinal events than because of any other class of events.
Treatment-related adverse events in patients with refractory invasive fungal infections that resulted in the discontinuation of treatment, discontinuation of the study, or death.
Serious adverse events. Overall, 35 (8%) of 428 patients reported any treatment-related serious adverse event. Most individual events occurred in <1% of patients and involved the cardiac, neurologic, or hepatic systems or were associated with potential drug reactions. Serious adverse events that occurred in ⩾1% of patients were altered drug level (digitalis in 1 patient, cyclosporine in 1 patient, and tacrolimus in 2 patients), increased hepatic enzymes (4 patients), nausea (3 patients), rash (3 patients), and vomiting (3 patients). Tacrolimus toxicity was reported in 1 patient, and cyclosporine toxicity was reported in 1 patient. No treatment-related serious adverse events were observed in any group in the dose-finding study.
Of particular note, convulsions were considered to be related to posaconazole treatment for 2 patients (<0.5%). One patient had a prior history of convulsions and had received concomitant cyclosporine (see below), and the other patient with convulsions received concomitant tacrolimus. Serum levels of tacrolimus for the second patient (on day 5 of posaconazole treatment) were 5.6 ng/mL. Posaconazole and tacrolimus were discontinued, and no additional convulsions were reported.
Four patients (<1%) also had treatment-related serious adverse events of the renal and/or urinary system, including acute renal failure with increased blood creatinine concurrent with tacrolimus toxicity, renal failure concurrent with grade 4 pancreatitis in a patient with a history of renal dysfunction, renal failure and nephrotoxicity concurrent with cyclosporine elevation, and abnormal urine (choluria) in conjunction with hepatic failure.
Deaths. A total of 157 patients (37%) among the overall population of patients died. The most common causes of death were adverse events that were considered to be unrelated to the study treatment (75 patients). In most instances, these adverse events were attributable either to complications of the patient's underlying disease or to progression of the disease under investigation. Seventy-seven deaths were directly attributed to the disease under investigation or progression of the disease under investigation, and 3 deaths were attributed to other causes (complications due to AIDS, unknown cause after the patient was discharged to hospice, and end-stage chronic obstructive pulmonary disease).
Two deaths were considered to be possibly related to posaconazole treatment because of temporal relationships between administration of drug and the adverse events that led to death. One death occurred in a 16-year-old female recipient of a bone marrow transplant who died of respiratory failure after a seizure that occurred 1 day after the last dose of posaconazole, on day 95. This patient had a history of seizures and had a prolonged seizure at home that resulted in hospitalization with coma, followed by multiple organ failure and death. This event was considered likely to be a recurrence of seizures that occurred during posaconazole therapy. The other death involved a 38-year-old male patient, who was found to be unresponsive while sleeping at home after day 119 of posaconazole treatment. This patient had a previous history of type I diabetes, hypoglycemic episodes, end-stage renal disease, and renal transplant 4 months before study entry. No autopsy or laboratory studies were performed. Although the respective investigators could not rule out posaconazole as a possible cause, these events are considered more likely to be related to preexisting medical conditions or intercurrent infections.
Adverse events associated with long-term posaconazole treatment. As shown in table 2, many common treatment-related adverse events (such as anorexia, headache, menstrual disorder, and increased serum glutamic pyruvic transaminase levels) occurred at slightly higher rates among the population receiving long-term posaconazole treatment than they did among the population receiving short-term treatment. However, rates of certain grade 3 or 4 adverse events, such as respiratory insufficiency, multiple organ failure, cardiorespiratory arrest, hypotension, and coma, were lower in patients who received longer treatment. No trend in treatment-related adverse events suggested increasing risk of any adverse event with longer treatment.
Hematologic data. Most patients among the overall population had abnormal baseline values (CTC grade 1 or higher) for hematocrit, hemoglobin, and platelet levels and slightly more than one-half had abnormal baseline values for neutrophil counts or leukocyte counts. Changes from grades 0, 1, or 2 to grades 3 or 4 at any time during treatment are shown in table 4.
Shifts in hematologic and blood chemistry values from Common Toxicity Criteria grades 0, 1, or 2 at baseline to grades 3 or 4 as the worst value during posaconazole treatment in patients with refractory invasive fungal infections.
Blood chemistry data. Potentially clinically important shifts in blood chemistry values for patients with baseline measurements and at least 1 post-baseline measurement are also reported in table 4. Approximately 25% of patients had abnormal values for liver parameters at baseline, and 40% had increased creatinine values at baseline. No trends suggested adverse laboratory effects were associated with longer exposure to posaconazole.
Cardiac safety data. A total of 265 patients had electrocardiogram findings recorded at baseline and at least 1 electrocardiogram finding recorded during posaconazole therapy, and 288 patients had at least 1 electrocardiogram finding recorded during treatment. Treatment-related adverse events included prolongation of the corrected QT (QTc) interval and/or the QT interval (among 1% of the overall population) and atrial fibrillation (among 1% of the overall population) that were generally mild to moderate in nature and did not lead to study discontinuation. Treatment-related QTc interval and/or QT interval prolongations occurred after 28–64 days of treatment and led to interruption of treatment (in accordance with protocol) for 2 patients. One instance of serious QTc interval and/or QT interval prolongation was considered to be related to either posaconazole, systemic lupus erythematosus, or renal failure. No increased risk of cardiac events was observed with posaconazole treatment for ⩾6 months.
Discussion
Posaconazole was found to have a favorable safety profile during treatment of seriously ill patients with IFIs. In these phase II/III trials, the most common adverse events considered possibly or probably related to treatment were gastrointestinal in nature. Other treatment-related adverse events that are known to be associated with the azole class occurred at low rates, including increased serum glutamic pyruvic transaminase levels (11 [3%] of 428 patients), altered drug levels (7 [2%] of 428 patients), QTc interval and/or QT interval prolongations (6 [1%] of 428 patients), and convulsions (2 [<0.5%] of 428 patients). Both patients with convulsions received concomitant cyclosporine or tacrolimus, and blood levels of these drugs are known to increase when they are coadministered with azoles [24–26]. Similar drug interactions have been reported with posaconazole [27].
In one of the most extensive evaluations of long-term therapy with an azole in a clinical development program, posaconazole safety was analyzed in 109 patients who received treatment for ⩾6 months. Of those, 27 patients received posaconazole treatment for >1 year. There are only a few reports of treatment for comparable durations with other agents in the azole class [28, 29]. These assessments are especially relevant for agents used to treat patients with IFIs, who may require weeks or months of prophylaxis or therapy to achieve prevention, improvement, or cure. Our investigation did not suggest increased risk of any adverse event, and no unique treatment-related adverse event was observed with longer exposure to posaconazole.
A total of 157 (37%) of 428 patients died during the course of the 2 studies. Adverse events leading to death were reported as possibly related to posaconazole treatment for 2 patients because of temporal association with therapy, but were more likely to be related to preexisting medical conditions. The risk of death and discontinuation was not different for those patients who received short-term posaconazole versus long-term posaconazole. The high death and discontinuation rates are not unexpected among this very ill patient population, who were considered for salvage therapy because previous antifungal therapies had failed or because they could not tolerate the therapy. Many received posaconazole therapy until death, because there were no alternative treatments.
The polyene antifungal agents, amphotericin B and its lipid formulations, are still a mainstay of therapy for serious fungal infections, but their use is associated with considerable renal toxicity and infusion-related adverse events [30].
Voriconazole was introduced in 2002 and has proven efficacy for many fungal infections [31, 32], but possible development of serum level—related hepatic toxicity is a safety concern [31, 33], and transient visual disturbances are reported in as many as 45% of patients in clinical studies [30]. A new class of antifungal agents, the echinocandins, is represented by caspofungin, micafungin, and anidulafungin. The spectrum of activity of echinocandins is limited to infection with Aspergillus species and Candida species [34]. Echinocandins have limited activity against the newly emerging molds, such as Fusarium species, Scedosporium species, and zygomycetes [35, 36]. In addition, several yeasts, such as Cryptococcus neoformans, Trichosporon species, and Rhadotaorulo species are relatively resistant to echinocandins [37–39].
Posaconazole has been shown to have broad-spectrum in vitro and clinical activity against various yeasts and molds causing IFI [3]. In this study, the long-term use of posaconazole had a safety profile comparable to that of its short-term use. In a recent study, posaconazole had a similar safety profile and tolerability, compared with fluconazole, during treatment for oropharyngeal candidiasis in patients with HIV/AIDS [40]. This is of paramount importance, because the safety, tolerability, and oral bioavailability of this drug are all factors that contribute to its long-term successful use in the prolonged outpatient prophylaxis or treatment of IFIs [1, 12, 14, 21, 22].
We conclude that the safety profile of posaconazole justifies its use in salvage treatment for critically ill patients with IFI. Also, the safety and tolerability of long-term posaconazole use suggest that evaluation of this active drug for prophylactic and/or primary antifungal treatment is warranted.
Principal Investigators
The following individuals participated in these studies as principal investigators. H. Al-Abdely (Section of Infectious Diseases, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia), R. Avery (Cleveland Clinic Foundation, Cleveland, OH), C. Bachier (Southwest Texas Methodist Hospital, San Antonio), J. Blumer (University Hospitals of Cleveland, Cleveland, OH), M. Brunvard (HealthONE Presbyterian/St. Luke's Hospital, Denver, CO), A. Buchbinder (North Shore University Hospital, Manhasset, NY), A.B. Bustamante (Hospital Nacional Cayetano Heredia, Lima, Peru), A. Catanzaro (UCSD Medical Center, San Diego, CA), G. Connaghan (Blood and Marrow Transplant Group of Georgia, Atlanta), O. Cornely (Universitaet Koeln, Koeln, Germany), J. Daly (University of Massachusetts Medical Center, Worcester), S. M. Devine (University of Illinois at Chicago, Chicago), J. Galgiani (Southern Arizona VA Healthcare System, Tucson), H. Gallais (Hôpital de la Conception, Marseille, France), V. Gaona-Flores (Hospital de Infectologia, CMN La Raza, La Raza, Mexico), M. Gardner (St. Mary's Health Center, St. Louis, MO), H. Goodpasture (Wesley Medical Center, Wichita, KS), D. Graham (Springfield Clinical Research, Springfield, IL), J. Graybill (University of Texas Health Science Center, San Antonio), M. Green (University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, PA), S. Green (Royal Hallamshire Hospital, Sheffield, United Kingdom), R. Greenberg (University of Kentucky Medical Center, Lexington), S. Hadley (New England Medical Center, Boston, MA), R. Herbrecht (CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France), J. Hiemenz (Walt Disney Memorial Cancer Center, Orlando, FL), M. Hoglund (Akademiska Hospital, Uppsala, Sweden), S. Homann (St. Anthony Medical Center, Rockford, IL), R. Hsu (St. Vincent's Hospital, New York, NY), R. Hudson (Hudson Medical Group, Atlanta, GA), A. Jandourek (Henry Ford Hospital, Detroit, MI), M. Joyce (Nemours Children's Clinic, Jacksonville, FL), H. Kantor (Texas Tech Internal Medicine Clinic, Odessa), A. Kisch (St. Barnabas Medical Center, Livingston, NJ), H.-G. Klingemann (Rush Medical College, Chicago, IL), A. Langston (Emory University Hospital, Atlanta, GA), P. T. Ljungman (Karolinska University Hospital, Huddinge, Sweden), K. Marr (Fred Hutchinson Cancer Center, University of Washington Seattle, Seattle), R. Martinez (Universidade de Sao Paulo, Ribeirao Preto, Brazil), N. Milpied (Hotel Dieu CHRU de Nantes-Service d'Hematologie Clinique, Nantes, France), M. Montiel (Hospital Militar Central, Lima, Peru), T. Moore (Center of Infectious Disease, Wichita, KS), H. Myint (Rush Medical Center, Chicago, IL), R. Negroni (Hospital Muňiz, Buenos Aires, Argentina), M. Netherda (Center for HIV Prevention and Care, Santa Rosa, CA), N. Novitzky (Southern Cross Hospital, Cape Town, South Africa), E. Ong (Newcastle General Hospital, Newcastle upon Tyne, UK), J. Perfect (Duke University Medical Center, Durham, NC), F. Petersen (University of Utah, Salt Lake City), A. Pigneux (Hôpital Haut Leveque, Pessac, France), P. Pitisuttithum (Mahidol University, Bangkok, Thailand), K. Presberg (Froedtert Memorial Lutheran Hospital, Milwaukee, WI), I. Raad (University of Texas MD Anderson Cancer Center, Houston), A. Reboli (Cooper Hospital, University Medical Center, Camden, NJ), A. Rendon-Perez (Hospital Universitario Dr. JE Gonzalez, Monterrey, Mexico), A. Restrepo (Clínica Cardiovascular Colombiana, Medellín, Colombia), P. Ribaud (Hospital Saint Louis, Paris, France), W. Rozenbaum (Hôpital Rothschild-Service des Maladies Infectieuses, Paris, France), R. Sanchez-Lopez (Centro de Investigaciones Medicas Asociadas, Hermosillo, Son Mexico), I. Sanne (University of the Witwatersrand, Johannesburg, South Africa), G. Schiller (UCLA School of Medicine, Los Angeles), M. Schirmer (Instituto Nacional Do Cances, Rio de Janiero, Brazil), S. Tarantolo (University of Nebraska, Omaha), H. Tissot-Dupont (Service de Maladies Infectieuses, Marseille, France), P. Tutschka (University of Connecticut Health Center, Farmington), A. J. Ullmann (Medizinische Klinik und Poliklinik der Johannes Gutenberg-Universität Mainz, Mainz, Germany), J.-A. H. van Burik (University of Minnesota School of Medicine, Minneapolis), D. H. Vesole (Medical College of Wisconsin, Milwaukee), J. Wingard (University of Florida, Gainesville), M. Wong (Beth Israel Deaconness Medical Center, Boston, MA), I. Yakoub-Agha (Regional University Hospital Complex, Lille, France), S. Yasuda (Hospital Das Clinicas Da FMUSP, Sao Paolo, Brazil), and P. Zakowski (Cedars-Sinai Medical Center, Los Angeles, CA).
Acknowledgments
We acknowledge the assistance of Elizabeth Downs and Cathy Bruno in preparation of the manuscript.
Financial support. These studies were part of the clinical development program for posaconazole and were supported and carried out by Schering-Plough Research Institute.
Potential conflicts of interest. I.I.R. has received recent research funding from Schering-Plough and Wyeth-Ayerst; serves as a consultant for Vicuron and Peninsula Pharmaceuticals; and is on the speakers' bureaus for Merck, Pfizer, Astellas, and Wyeth-Ayerst. J.R.G. has received research grants from Merck, Schering-Plough, NeuTech Pharma, Astellas, and Pfizer and has performed research work for Indevus; is on advisory committees for Merck, Schering-Plough, Indevus, and Pfizer; and is a speaker for Merck. A.B.B. has received research funding from Fujisawa Healthcare and Novartis. O.A.C. has received research funding from, is a consultant for, and is a member of speakers' bureaus for Astellas, Gilead, Merck, Pfizer, and Schering-Plough; has received research funding from and is a consultant for Basilea and Vicuron; and is a consultant for Zeneus. D.R.G. has received recent research funding from Vicuron, Wyeth, Schering-Plough, and Pfizer; is a consultant for Vicuron and Wyeth; and is on the speakers' bureaus for Wyeth, Pfizer, and Aventis. R.N.G. has received recent research funding from Boehringer Ingelheim, BMS, Schering-Plough, Merck, Dynport, Acambis, Vaxgen, Bavarian-Nordic, Astellas, GSK, Tibotec, and VirXsys. S.H. has received recent research funding from Enzon (formerly The Liposome Company), Astellas (formerly Fujisawa), Ortho-Biotech, Pfizer, and Schering-Plough and is a consultant for Schering-Plough, Merck, and Enzon. S.H. is on the speakers' bureaus for Merck, Pfizer, and Astellas. A.L. has received research funding and is a consultant for Schering-Plough. J.R.P. has received research funding from, is a consultant for, and is on the speakers' bureaus for Merck, Astellas, Pfizer, Schering-Plough, Enzon, and Pliva. G.S. is a consultant for Wyeth-Ayerst, CI, and Johnson & Johnson. L.P. is an employee of Schering-Plough. A.J.U. has received recent research funding from Schering-Plough and is a consultant for Schering-Plough, MSD, Pfizer, Astellas, Gilead, and Basilea. A.J.U. is on the speakers' bureaus for Schering-Plough, MSD, Pfizer, Astellas, and Gilead. All other authors: no conflicts.
References
Principal investigators are listed at the end of the text.
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