The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation.

On October 24, 2019, a marketing authorization valid through the European Union (EU) was issued for gilteritinib monotherapy for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication (ITD), FLT3 D835Y, and FLT3 ITD D835Y, and it induced apoptosis in leukemic cells expressing FLT3 ITD. The recommended starting dose of gilteritinib is 120 mg (three 40 mg tablets) once daily. Gilteritinib was evaluated in one, phase III, open-label, multicenter, randomized study of gilteritinib (n = 247, gilteritinib arm) versus salvage chemotherapy (n = 124, salvage chemotherapy arm) in patients with relapsed or refractory AML with FLT3 mutation. Overall survival (OS) was statistically significantly different between the two groups with a median OS of 9.3 months in the gilteritinib arm compared with 5.6 months for salvage chemotherapy (hazard ratio, 0.637; 95% confidence interval, 0.490-0.830; p = .0004 one-sided log-rank test). The most common adverse reactions with gilteritinib treatment were blood creatine phosphokinase increase, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, diarrhea, fatigue, nausea, constipation, cough, peripheral edema, dyspnea, dizziness, hypotension, pain in extremity, asthenia, arthralgia, and myalgia. The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Xospata was approved in the European Union as monotherapy for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib resulted in a clinically meaningful and statistically significant improvement of overall survival compared with salvage chemotherapy. At the time of the marketing authorization of gilteritinib, there were no approved standard therapies specifically for adult patients diagnosed with relapsed or refractory AML with FLT3 mutation. In terms of safety, the overall accepted safety profile was considered manageable.

[Concomitant use of warfarin, analgesics and anti-inflammatory agents]. / Samtidig bruk av warfarin, analgetika og antiinflammatoriske midler.

BACKGROUND: Concomitant use of warfarin and analgesics enhances the risk of bleeding. The frequency of such co-medication has not yet been investigated. The main aim of the present study was to determine the prevalence of concomitant use of warfarin and prescription analgesic drugs in Norway. MATERIAL AND METHODS: All patients were included who were registered in the Norwegian Prescription Database as having received warfarin (Marevan) at Norwegian pharmacies from 2004 to 2006. Data were retrieved on prescription of warfarin and common analgesic drugs (paracetamol, weak opioids and NSAIDs). "Concomitant medication" was defined as the concurrent use of warfarin and analgesic drugs as prescribed by one or more different physicians at the same or different date, but within the time period for warfarin use. RESULTS: The number of warfarin users was approximately 80,000 in 2006 (60 % men), 93 % were older than 50 years and the majority were on long-term treatment. 25 % of warfarin patients used weak opioids in each of the following years: 2004, 2005 and 2006, while 16 - 23 % were on NSAIDs and 29 - 31 % on paracetamol. INTERPRETATION: A higher number of Norwegians is treated with warfarin than previously presumed. Concomitant use of common analgesics was likely for at least one fourth of the warfarin users. As the investigated analgesics may interact with and increase the effect of warfarin (through different mechanisms), the frequent co-prescribing of these drugs may be associated with an increased risk of bleeding.

Adherence to medication guideline criteria in cancer pain management.

The medication-assessment tool for cancer pain management (MAT-CP) is a novel tool for measuring the quality of drug use in chronic pain management in relation to guideline standards. MAT-CP has recently been revised and validated for use in the U.K. clinical setting. This article presents a measure of the adherence of current practice to specific cancer pain guideline criteria in two palliative care settings. Adult patients with malignant disease experiencing pain and/or receiving analgesics were identified by clinical pharmacists at two hospitals and five hospices in Scotland, United Kingdom. The MAT-CP was applied to data extracted from case notes. Results were quantified in terms of applicability and adherence to guideline criteria and the presence of insufficient data. MAT-CP was applied to 192 cancer patients experiencing pain; 103 (54%) were males and the mean (standard deviation) age was 68.5 (13.0) years. Overall guideline adherence was 75% (confidence interval [CI]: 74%, 77%; n=3460 applicable criteria). Low adherence (<50%) was seen for nine criteria, whereas 21 criteria were considered high-adherence criteria (>75%). Overall adherences for 56 (29%) hospitalized patients and 136 (71%) hospice patients were 65% (CI: 62%, 68%) and 79% (CI: 78%, 81%), respectively. Although good overall guideline adherence was found, there were gaps in both the hospice and hospital palliative care settings in the implementation of certain treatment recommendations, particularly in relation to pain assessment. The application of the tool has highlighted issues for feedback to health care providers and for further study.

Design and validation of a medication assessment tool for cancer pain management.

OBJECTIVE: A clinical tool to examine prescribing in cancer pain management may provide a means to help establish acceptable standards of adherence to treatment guidelines. The study aim was to design and validate a Medication Assessment Tool for Cancer Pain Management (MAT-CP). SETTING: Hospitals in Northern Norway METHOD: The MAT-CP was designed from guideline criteria based on a previously developed method. The tool was validated by peer review before and during field-testing on a study sample of cancer patients experiencing pain. MAIN OUTCOME MEASURE: Perceived relevance, utility, and clarity of individual criteria, and reliability of their application to clinical documentation. Frequency of adherence to agreed definitions of guideline criteria. RESULTS: The final tool comprised 36 criteria covering six different aspects of cancer pain management: (1) pain assessment and information transfer, (2) start of strong opioid therapy; (3) current continuous analgesia; (4) current intermittent analgesia; (5) follow-up of therapy, and; (6) other care issues. The tool was tested on 109 cancer patients experiencing pain (57 males), mean (SD) age 60.8 (11.5) years. Guideline adherence overall was 61% (n=1704 applicable criteria). The field-testing informed the modification of the MAT-CP to optimise its clarity and utility when applied to patients' clinical documentation. Good inter- and intra-rater reliability (Cohen's kappa kappa=0.86 and kappa=0.95, respectively) were demonstrated in the application. The preliminary application of the tool during field-testing has highlighted the following for further study: (a) Low adherence <50%) to 14 standards concerning start of opioid treatment and pain therapy follow-up, clinical assessment of risk of gastro-intestinal adverse effects among patients on non-steroidal anti-inflammatory drugs (NSAID), current treatment of breakthrough pain, management of nausea/vomiting; (b) High adherence (>75%) to standards of prescribing of continuous analgesia. CONCLUSION: A clinical tool to examine prescribing in cancer pain management has been designed. Face and content validity have been informed by field-testing. The tool requires further study among palliative care specialists as part of the validation required before it can be recommended for clinical use.