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An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic.

ABSTRACT: Omadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.

SUBMITTER: Opal S

PROVIDER: S-EPMC6669290 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic.

Opal Steven S File Thomas M TM van der Poll Tom T Tzanis Evan E Chitra Surya S McGovern Paul C PC

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190801 Suppl 1

Omadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Packag ...[more]

PMID: 31367740

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Project description:Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 ?g · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 ?g · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 ?g · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 ?g/ml when it was administered after dialysis and 2.33 ?g/ml when it was administered before dialysis, and in healthy subjects it was 1.92 ?g/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

Project description:BackgroundOmadacycline is an oral and intravenous (IV) once-daily aminomethylcycline antibiotic that was recently approved by the US Food and Drug Administration for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). In 2 phase 3 clinical trials, IV-to-oral switch and oral-only administration of omadacycline achieved the primary end points of noninferiority compared with linezolid in treating patients with ABSSSI.ObjectiveTo estimate the potential cost-savings with bioequivalent IV-to-oral antibiotics, such as omadacycline, compared with the standard of care with IV vancomycin by avoiding hospitalizations and reducing hospital stays in patients presenting from the emergency department for ABSSSI treatment.MethodsWe used hospital avoidance models to examine the potential cost-savings of managing patients with ABSSSI and no or limited comorbidities and without life-threatening conditions by using omadacycline in the outpatient setting compared with the current standard of care. Early hospital discharge models were used to evaluate the hospital stay reduction that would be required to be achieved with omadacycline treatment relative to IV vancomycin to confer cost-savings compared with standard of care among patients with ABSSSI and ?2 comorbidities but no life-threatening conditions.ResultsIn the hospital stay avoidance models, cost-savings may be realized by using therapeutically bioequivalent IV-to-oral antibiotics, such as omadacycline, compared with inpatient treatment with IV vancomycin. Based on a sensitivity analysis, further savings could be possible with outpatient administration of omadacycline, even if 20% of omadacycline outpatients were subsequently admitted and incurred the full inpatient cost, with no reimbursement penalties. Of more than 300 patients, only 1 was admitted to the hospital after a full course of omadacycline in the oral-only clinical trial. In the early hospital discharge models, the maximum cost-minimizing daily expense of omadacycline varied from $173 to $936, depending on the presence of active comorbidities or systemic symptoms, hospital stay reduction, and model perspective.ConclusionThese results suggest that the targeted use of antibiotics with bioequivalent IV-to-oral formulations, such as omadacycline, for select patients with ABSSSI may lead to cost-savings compared with inpatient IV vancomycin treatment by shifting care to the outpatient setting or by facilitating earlier hospital discharge among hospitalized patients.

Project description:Background and aimsTofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme.MethodsPatients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated.ResultsIn total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09-0.46]; serious infections, 1.69 [1.26-2.21]; herpes zoster [non-serious and serious], 3.30 [2.67-4.04]; opportunistic infections, 1.03 [0.70-1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55-1.24]; NMSC, 0.73 [0.45-1.10]; MACE, 0.29 [0.13-0.55]; deep vein thrombosis, 0.03 [0.00-0.18]; pulmonary embolism, 0.19 [0.07-0.42]; gastrointestinal perforations, 0.10 [0.02-0.28].ConclusionsAESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 [2020] Cohort, with the exception of herpes zoster [a known risk of tofacitinib treatment]. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304JCC Topic/keyword selection: 3. Clinical trials.

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An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic.

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An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic.

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