isavuconazole and Drug-Related-Side-Effects-and-Adverse-Reactions

Invasive aspergillosis (also known as IA) is a type of fungal infection, caused by a species of fungus called. The results of this study showed that healthy Chinese people's bodies processed isavuconazole the same way as healthy Western people's bodies. The amount of drug in people's bodies did not change how well the drug worked or how many side effects there were. Isavuconazole worked as well as and had a similar number of side effects as voriconazole in treating Chinese patients with IA.. These findings show that isavuconazole may be a suitable treatment for Chinese patients with IA using the same dose that is used in Western patients.

Topics: Antifungal Agents; Aspergillosis; Drug-Related Side Effects and Adverse Reactions; Healthy Volunteers; Humans; Invasive Fungal Infections; Mycoses; Nitriles; Pyridines; Triazoles; Voriconazole

Invasive mucormycosis in immunocompromised children is a life-threatening fungal infection. We report a case of a 7-year-old girl treated for acute lymphoblastic leukaemia complicated by disseminated mucormycosis during induction therapy. Microscopic examination of surgically removed lung tissue revealed wide, pauci-septate hyphae suggesting a Mucorales infection. This diagnosis was confirmed immunohistochemically and by PCR analysis followed by a final identification of Cunninghamella sp. The patient was treated successfully with surgical debridement and antifungal combination therapy with amphotericin B, caspofungin and isavuconazole. The use of isavuconazole in a child was not previously reported. Additionally, case reports concerning pulmonary mucormycoses in paediatric population published after 2010 were reviewed. Nineteen out of 26 identified patients suffered from haematological diseases. Reported mortality reached 38.5%. By the fact of rising morbidity, unsatisfactory results of treatment and remaining high mortality of mucormycoses in immunocompromised patients, new therapeutic options are warrant. Isavuconazole, with its broad-spectrum activity, good safety profile and favourable pharmacokinetics, is a promising drug. However, further studies are necessary to confirm positive impact of isavuconazole on mucormycosis treatment in children.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Child; Cunninghamella; Debridement; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Hemochromatosis; Humans; Invasive Fungal Infections; Mucormycosis; Nitriles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Treatment Outcome; Triazoles

Isavuconazole is a new extended-spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was noninferior to that of voriconazole. An open-label trial that studied primary as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

Topics: Antifungal Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Invasive Pulmonary Aspergillosis; Mucormycosis; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles

Basilea Pharmaceutica is developing BAL-8557, a water-soluble prodrug of the triazole BAL-4815, for the potential treatment of fungal infections. By August 2005, a phase II study in oral candidiasis was underway. In September 2005, phase III trials were planned for invasive Candida and mold infections, including aspergillus and zygomycetes.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Humans; Nitriles; Pyridines; Triazoles

The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species.

Topics: Administration, Intravenous; Adult; Aged; Antifungal Agents; Aspergillosis; Aspergillus; Coinfection; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Mucorales; Mucormycosis; Nitriles; Pyridines; Treatment Outcome; Triazoles

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Antifungal Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Nitriles; Pyridines; Survival Analysis; Treatment Outcome; Triazoles; Young Adult

The authors present a case of a 67-year-old woman with primary biliary cirrhosis (Child-Pugh class B) who was treated with isavuconazole for invasive pulmonary and cerebral aspergillosis. Isavuconazole treatment was initiated with the standard maintenance dose of 200 mg daily. Therapeutic drug monitoring (TDM) was performed to target trough concentrations within the desired range of 1.0-5.13 mg/L.. Real-time TDM and pharmacokinetic analyses were used to determine the dose adjustments. Liver transaminases (alanine aminotransferase and gamma-glutamyl transferase) were assessed to monitor hepatotoxicity.. The trough plasma levels gradually increased over time up to 17.8 mg/L. TDM-guided clinical pharmacological advice was helpful to initially reduce the dose, then to temporarily suspend drug administration, and finally to calculate the correct dose that allowed for long-term treatment up to day 258. No major signs and/or symptoms of drug-related toxicity occurred, apart from a transient increase in gamma-glutamyl transferases that normalized after the drop in isavuconazole trough levels within the desired range.. TDM-guided clinical pharmacological advice was essential for the successful and safe management of isavuconazole treatment in this patient with moderate liver dysfunction.

Topics: Aged; Antifungal Agents; Aspergillosis; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Liver Cirrhosis, Biliary; Teaching Rounds

We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antifungal Agents; Child; Child, Preschool; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Mycoses; Nitriles; Pyridines; Serum; Sex Factors; Triazoles; United Kingdom; Young Adult

Posaconazole (PCZ) is widely used for prophylaxis or treatment of invasive fungal infections (IFIs) in leukaemia patients. However, issues with PCZ tolerability can result in treatment interruption. Isavuconazole (ISA) has a similar broad spectrum of activity to PCZ; however, real-world data regarding the tolerability of ISA after PCZ toxicity are lacking.. To describe the tolerability of ISA after PCZ toxicity in leukaemia patients.. We retrospectively assessed tolerability of ISA after PCZ toxicity in adult leukaemia patients (March 2015 to November 2017). We included all patients who received ≥7 days of ISA within 48 hours of PCZ discontinuation. Laboratory markers for liver toxicity were collected at three time points: prior to PCZ, at switch to ISA and after ISA therapy.. We identified 23 such patients. Increased liver function tests (LFTs) were noted in 20 patients on PCZ, while three patients had Grade 3/4 QTc prolongation. No patient discontinued subsequent ISA due to toxicity. Grade 3/4 elevations in LFTs were decreased after changing to ISA (30% after PCZ vs 5% after ISA). No patient had significant QTc prolongation after switching to ISA.. Isavuconazole was well-tolerated in patients discontinuing PCZ due to toxicity, with no patient discontinuing ISA due to toxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia; Liver Function Tests; Male; Middle Aged; Mycoses; Nitriles; Pyridines; Retrospective Studies; Triazoles; Young Adult

Long-term oral triazole antifungal therapy is the cornerstone of management for patients with chronic pulmonary aspergillosis (CPA). Itraconazole is the first-line choice of treatment. Voriconazole, posaconazole or isavuconazole can be used as alternative treatments in case of resistance or intolerance. All of these can cause significant adverse drug reactions.. To evaluate how CPA patients tolerate voriconazole and isavuconazole after prior triazole therapy.. We performed a retrospective observational study at the UK National Aspergillosis Centre. Medical records for all consecutive CPA patients started on isavuconazole and voriconazole during an observation period of 12 and 6 months respectively were analysed.. During this study period, 20 patients were started on isavuconazole and 21 patients on voriconazole. Adverse events were seen in 18 of 21 (86%) the patients in the voriconazole group and 12 of 20 (60%) in the isavuconazole group (P = 0.02). For those who developed adverse events to these agents, the rates of discontinuation of therapy were comparable (ie 10/18 [56%], voriconazole vs 8/12 [67%], isavuconazole; P = 0.54). Five (25%) patients in the isavuconazole group who were intolerant to other triazoles tolerated the standard dose of isavuconazole.. Compared with isavuconazole, adverse events were significantly higher in CPA patients commenced on voriconazole. Isavuconazole may be an option for those patients who are intolerant to other triazoles.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Chronic Disease; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nitriles; Pulmonary Aspergillosis; Pyridines; Retrospective Studies; Triazoles; United Kingdom; Voriconazole

Isavuconazole use in the real-world setting has not been extensively described. Subgroups of patients with particular prognostic significance, such as previous triazole prophylaxis or treatment and the important subgroup treated empirically for invasive fungal infection, have beforehand been excluded from trials.. We aimed to determine treatment response and safety in these patients at a large US transplant and cancer centre.. We conducted a retrospective cohort study of all adult inpatients administered ≥3 doses of isavuconazole between June 2015 and October 2017.. Ninety-one adults were identified. Six (7%) received primary prophylaxis, 10 (11%) treatment then secondary prophylaxis and 75 (82%) treatment only. Overall treatment response was 62%. Six-week mortality was 24%. Sixty-three per cent of 32 patients treated with isavuconaozle following prophylaxis with another antifungal agent exhibited a treatment response. Among 49 patients switched from treatment with another agent, 53% had a treatment response. Thirty-four patients received isavuconazole empirically, and 65% demonstrated a treatment response. Individuals given isavuconazole prophylaxis developed no breakthrough invasive fungal infections. One patient discontinued isavuconazole due to hepatotoxicity.. Real-world isavuconazole use appears safe and is associated with treatment responses in varied patients including critically important subgroups previously unreported.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Antifungal Agents; Chemoprevention; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Mycoses; Nitriles; Pyridines; Retrospective Studies; Survival Analysis; Treatment Outcome; Triazoles; United States

Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients.. To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity.. From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity.. A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64-8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023-0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity.. Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; ROC Curve; Serum; Triazoles