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

Invasive fungal infections are a major cause of morbidity and mortality in children with hematological malignancies and those undergoing allogeneic hematopoietic stem-cell transplantation (HSCT). Although several new antifungal compounds recently became available, some are not yet approved for the use in the pediatric population. Among the new class of echinocandins, micafungin has been licensed in Europe and Japan for children including neonates. Because micafungin is well tolerated and exhibits few clinical relevant drug-drug interactions, the compound is of particular interest for prophylaxis and treatment of invasive mycoses in pediatric patients with cancer or following allogeneic HSCT. This review will focus on the currently available pediatric data of micafungin with emphasis on pharmacokinetics, efficacy, and safety.

Topics: Antifungal Agents; Child; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Hematologic Neoplasms; Humans; Lipopeptides; Micafungin; Mycoses; Treatment Outcome

Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk.. In this open-label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests.. The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score ≥20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Δ standard care - micafungin [95% confidence interval], 0.7% [-2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (-2.9% [-8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care-treated patients.. Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin.. NCT01058174.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Chemoprevention; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Humans; Kidney Function Tests; Lipopeptides; Liver Function Tests; Liver Transplantation; Male; Micafungin; Middle Aged; Mycoses; Transplant Recipients; Treatment Outcome; Young Adult

The safety and efficacy profile of caspofungin and micafungin in Japanese patients with fungal infections were directly compared in this prospective, randomized, double-blind study. The proportion of patients who developed significant drug-related adverse event(s) (defined as a serious drug-related adverse event or a drug-related adverse event leading to study therapy discontinuation) was compared in 120 patients [caspofungin 50 mg, or 50 mg following a 70-mg loading dose on Day 1 (hereinafter, 70/50 mg) group: 60 patients; micafungin 150 mg: 60 patients]. The overall response rate was primarily evaluated in the per-protocol set (PPS) population. The proportion of patients who developed significant drug-related adverse events was 5.0 % (3/60) in the caspofungin group and 10.0 % (6/60) in the micafungin group [95 % confidence interval (CI) for the difference: -15.9 %, 5.2 %]. The favorable overall response in the PPS population for patients with esophageal candidiasis, invasive candidiasis, and chronic pulmonary aspergillosis including aspergilloma was 100.0 % (6/6), 100.0 % (3/3), and 46.7 % (14/30) in the caspofungin group, and 83.3 % (5/6), 100.0 % (1/1), and 42.4 % (14/33) in the micafungin group, respectively. In Japanese patients with Candida or Aspergillus infections, there was no statistical difference in the safety between caspofungin and micafungin. Consistent with other data on these two agents, the efficacy of caspofungin and micafungin was similar.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Humans; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Treatment Outcome

Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high-performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non-Hodgkin's lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Antineoplastic Agents; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Kidney Diseases; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long-term oral triazole therapy is unfeasible.. We evaluated the safety and efficacy of micafungin administered via the outpatient parenteral antimicrobial therapy (OPAT) service for the treatment of CPA.. We included all CPA patients who received micafungin via OPAT between April 2016 and March 2018. Data on adverse events and line-related complications, and Quality of Life (QoL) scores at the start of micafungin course and 3 months later were extracted. Improvements in QoL were defined as an improvement of ≥4 points in at least one modality (symptom, impact, activity, total) in the St George's QoL score. A stable QoL score was defined as a change in score of <4 points in either direction whilst deterioration was defined as an increase of ≥4 points.. There were 20 OPAT episodes involving 18 patients with a median duration of micafungin therapy of 21 (range: 4-248) days. Improvement or stability in the symptoms, activity, impact and total score was seen in 14 (78%), 12 (67%), 9 (50%) and 9 (50%) of the patients, respectively. However, half of the patients reported deterioration in the impact domain and total scores. By self-assessment, patients who categorised themselves as "poor" were comparable at the start of OPAT and at 3 months (43% vs 50%, McNemar's P = 0.7). Adverse events attributable to micafungin were recorded in 3 (14.3%) episodes.. Micafungin may be safely administered via an OPAT service. Micafungin therapy was associated with an improvement or stability in QoL scores in at least 50% of the patients across the four domains.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Ambulatory Care; Antifungal Agents; Chronic Disease; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Micafungin; Middle Aged; Outpatients; Pulmonary Aspergillosis; Quality of Life; Retrospective Studies; Treatment Outcome

This prospective, observational, multicenter study evaluated the real-world incidence of invasive fungal infection (IFI) during and after micafungin prophylaxis in France. Patients with a hematological malignancy/solid tumor received micafungin prophylaxis according to usual clinical practice and were followed for 3 months. Primary endpoint was breakthrough IFI incidence during prophylaxis. Secondary endpoints included the identification of IFI risk factors, IFI incidence during follow-up, and adverse events (AEs). One hundred and fifty patients (55 children, 95 adults) were enrolled. Micafungin prophylaxis was initiated at 50 mg in adults and at a median 1.01 mg/kg (range: 0.6-2.2) in children. Fifteen patients (10%) experienced an IFI during prophylaxis. IFI breakthrough occurred in 15% children, 7% adults, 3.1% allogeneic transplant patients, 8.7% acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients, 7.0% other patients (never allotransplanted/non-AML/MDS). Nineteen patients (12.7%) experienced an IFI during 3-month follow-up. Micafungin was well tolerated with few treatment-related AEs, supporting its use in this patient population in France.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Chemoprevention; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; France; Hematologic Neoplasms; Humans; Incidence; Infant; Invasive Fungal Infections; Longitudinal Studies; Male; Micafungin; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Invasive fungal infections are responsible for significant morbidity and mortality. Safety and effectiveness of antifungal agents is a particular concern in pediatric populations, where data are often limited. Micafungin is an echinocandin with demonstrated antifungal activity against a wide spectrum of Candida spp.; this subanalysis of data from the MYRIADE study describes the use of micafungin and its therapeutic outcomes in pediatric patients, in normal clinical practice.. MYRIADE was an observational, multicenter, national, prospective, longitudinal study conducted from January 2010 to December 2012, in patients treated with micafungin using a prophylactic or curative strategy, across 17 sites [oncohematology (n = 8), neonatal intensive care units (ICUs) (n = 5) and pediatric ICUs (n = 4)]. The treatment regimen, the achievement of the therapeutic objective and the tolerance were reported.. The study population consisted of 110 pediatric patients (31 neonates, 24 children <2 years old and 55 children ≥2 to <16 years old). The therapeutic objective was achieved in 49/64 (76.6%) oncohematology patients, 28/29 (96.6%) neonatal ICU patients and 12/14 (85.7%) pediatric ICU patients. Twenty-four (21.8%) children developed an adverse event (AE); more AEs were observed in oncohematology patients compared with ICU patients [17 (26.1%) vs. 7 (15.6%)]. Only one serious AE, reported in an oncohematology patient, was considered related to micafungin.. In the first large observational study of micafungin treatment or prophylaxis conducted under real-world conditions in France, micafungin was effective and well tolerated for prophylaxis of invasive fungal infections in pediatric oncohematology patients and for curative purposes in pediatric and neonatal ICU patients.

Topics: Adolescent; Antifungal Agents; Candida; Candidiasis, Invasive; Chemoprevention; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; France; Humans; Infant; Infant, Newborn; Longitudinal Studies; Male; Micafungin; Prospective Studies; Treatment Outcome

Micafungin (MCFG) is used for the prophylaxis of invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, the safety, efficacy, or optimal dosage/blood levels as prophylaxis is uncertain in pediatric HSCT-patients.. We prophylactically administered MCFG at 2 mg/kg once daily to 38 children and adolescents undergoing allogeneic HSCT.. During MCFG prophylaxis, infusion reactions or adverse events (grades 2-5) related to MCFG use were not found in all the patients. Thus, MCFG prophylaxis was not discontinued and other antifungal agents were not added except for 2 patients in whom probable or possible IFDs developed (completion rate, 94.7 %). To elucidate the influence of HSCT-related complications/drugs on blood concentration of MCFG, we determined the plasma trough and peak levels in 13 and 10 among 38 patients, respectively. The mean trough and peak levels were 3.04 ± 1.21 μg/mL (569 samples) and 9.63 ± 3.62 μg/mL (44 samples), respectively. The peak levels were moderately correlated to the trough levels (R (2) = 0.466). In a patient, the trough level of MCFG transiently increased up to 10.21 μg/mL during hepatic dysfunction due to acute graft-versus-host disease. The MCFG trough levels strongly correlated with T-Bil value (R (2) = 0.894). There was no relationship between the trough levels of MCFG and the circulating concentrations of tacrolimus (R (2) = 0.040). Additionally, MCFG levels were not influenced by treatment with cyclophosphamide or corticosteroids.. Prophylaxis with MCFG at 2 mg/kg once daily may be safe, tolerable, and feasible in pediatric HSCT-patients.

Topics: Adolescent; Antifungal Agents; Chemoprevention; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lipopeptides; Male; Micafungin; Mycoses; Plasma

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Topics: Antifungal Agents; Candidiasis; Double-Blind Method; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Europe; Humans; Lipopeptides; Liver Failure; Micafungin; Randomized Controlled Trials as Topic

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