Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data.

Gilteritinib has been approved as monotherapy in adults with acute myeloid leukemia (AML) FLT3 mutated with relapsed or refractory disease, in light of its advantages in terms of survival and the favorable safety profile. Hepatobiliary disorders and musculoskeletal and connective tissue disorders represent the most frequent adverse reactions associated with gilteritinib, whereas the most frequent serious adverse reaction is acute kidney injury. In the summary of product characteristics, gastrointestinal (GI) events are indicated as very common, in particular diarrhea, nausea and stypsis. Furthermore, serious GI disorders have been observed with gilteritinib in clinical trials, including GI hemorrhage, GI perforation and GI obstruction. However, the association with the FLT3 inhibitor has not been confirmed. Nevertheless, serious GI AEs have been recognized as an important potential risk to be monitored in postmarketing surveillance. We present three cases of serious self-limiting GI events observed in patients on gilteritinib treatment for AML, and an analysis of relevant available postmarketing surveillance data.

The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries.

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing-remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the "added value" compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score ("additional benefit not proven/no clinical improvement"), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings.

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database.

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5-12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.

Health Technology Assessment of Advanced Therapy Medicinal Products: Comparison Among 3 European Countries.

Even for centrally approved products, each European country is responsible for the effective national market access. This step can result in inequalities in terms of access, due to different opinions about the therapeutic value assessed by health technology assessment (HTA) bodies. Advanced therapy medicinal products (ATMPs) represent a major issue with regard to the HTA in order to make them available at a national level. These products are based on genes, tissues, or cells, commonly developed as one-shot treatment for rare or ultrarare diseases and mandatorily authorized by the EMA with a central procedure. This study aims to provide a comparative analysis of HTA recommendations issued by European countries (France, Germany, and Italy) following EMA approval of ATMPs. We found a low rate of agreement on the therapeutic value (in particular the "added value" compared to the standard of care) of ATMPs. Despite the differences in terms of clinical assessment, the access has been usually guaranteed, even with different timing and limitations. In view of the importance of ATMPs as innovative therapies for unmet needs, it is crucial to understand and act on the causes of disagreement among the HTA. In addition, the adoption of the new EU regulation on HTA would be useful to reduce disparities of medicine's assessment among European countries.

Rituximab in Multiple Sclerosis: Are We Ready for Regulatory Approval?

Despite the availability of a lot of effective disease-modifying drugs, multiple sclerosis (MS) (in particular the progressive forms) still represents an important unmet medical need, because of issues in terms of effectiveness, duration of response, safety, and patient compliance. An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance. To date, the use of rituximab in patients with multiple sclerosis is not in accordance with the authorized product information (off-label use). However, the use of this medicine is widespread in several countries, and in some cases, it is the most commonly used disease-modifying drug for MS subtypes. This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.

Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue.

Fertility preservation represents one important goal of cancer patients' management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.

Access to Innovative Neurological Drugs in Europe: Alignment of Health Technology Assessments Among Three European Countries.

Even for products centrally approved, each European country is responsible for national market access after European Medicines Agency (EMA) approval. This step can result in inequalities in terms of access, due to different opinions about the therapeutic value assessed by Health Technology Assessment (HTA) bodies. This study aims to provide a comparative analysis of HTA recommendations issued by EU countries (France, Germany, and Italy) for new neurological drugs following EMA approval. In the reference period, we identified 11 innovative medicines authorized in Europe for five neurological diseases (cerebral adrenoleukodystrophy, spinal muscular atrophy, metachromatic leukodystrophy, migraine, and polyneuropathy in patients with hereditary transthyretin amyloidosis), including eight drugs for genetic rare diseases. We found no agreement on the therapeutic value (in particular the "added value" compared to the standard of care) of the selected drugs. Despite the differences in terms of assessment, the access has been usually guaranteed even if with various types of limitations. The heterogeneity of the HTA assessment of clinical data among countries is probably related to the uncertainties about clinical value at the time of EMA approval and the lack of long-term data and of direct comparison with available alternatives. Given the importance of new medicines especially for rare diseases, it is crucial to understand and act on the causes of inconsistency among the HTA assessments, in order to ensure rapid and uniform access to innovation for patients who can benefit.

Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML.

The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is responsible of variable clinical manifestations, ranging from no symptoms to severe pneumonia with acute respiratory distress syndrome, septic shock, and multi-organ failure resulting in death. To date no specific antiviral drug have been approved for COVID-19, so the treatment of the disease is mainly focused on symptomatic treatment and supportive care. Moreover, there are no treatments of proven efficacy to reduce the progression of the disease from mild/moderate to severe/critical. An activation of the coagulation cascade leading to severe hypercoagulability has been detected in these patients, therefore early anticoagulation may reduce coagulopathy, microthrombus formation, and the risk of organ damages. The role of heparin in COVID-19 is supported by a lot of studies describing its pleiotropic activity but it must be proven in clinical trials. Several protocols have been designed to assess the risk-benefit profile of heparin (low-molecular-weight or unfractionated heparin) in hospitalized subjects. Although prophylactic doses may be adequate in most patients, it is important to wait the results of clinical trials in order to define the appropriate effective dose able to improve disease outcome.

Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: A systematic review of real-world studies.

INTRODUCTION: Systematic review of real-world studies about repeated dexamethasone intravitreal implant (DEXi) 0.7 mg in diabetic macular edema management, in order to identify the effective window of time occurring between injections, the critical evaluation of efficacy of the treatment, and the relative long-term safety in the real life setting. METHODS: Literature databases such as PubMed, SCOPUS, and EMBASE were used to identify reports including DEX implant injections. RESULTS: Twenty-one peer-reviewed publications were identified. DEX implants retreatment was considered on a pro re nata (PRN) basis at any time or starting from month three or four. About 1/3 of the eyes were retreated before six months from first injection (range 0-86.7%). Mean retreatment average time was 5.3 ± 0.9 months, with an estimated average of 1.3 injections each six months. There was no statistical correlation between average retreatment time and incidence of adverse events or other variables investigated. Limited safety issues related to implants number have been found, suggesting an overall good tolerance of long-term DEXi. CONCLUSIONS: Comprehensive evaluation of real-world data suggests an average DEXi duration close to five months, following a PRN treatment strategy, including about 1/3 of patients. Repeated DEXi administration revealed an acceptable long-term efficacy/safety ratio.

Pharmacokinetics of a new subcutaneous diclofenac formulation administered to three body sites: quadriceps, gluteus, and abdomen.

OBJECTIVE: To assess the relative bioavailability of a new subcutaneous (SC) diclofenac hydroxypropyl b-cyclodextrin (HPbCD) formulation administered to three body sites: quadriceps, gluteus, and abdomen. MATERIALS AND METHODS: This was a pilot, single-dose, randomized, three-way crossover relative bioavailability study. A total of 12 healthy subjects received a single SC injection of diclofenac HPbCD 50 mg/1 mL in the quadriceps, gluteus, or abdomen. RESULTS: The AUC was comparable after SC diclofenac HPbCD in the quadriceps, gluteus, and abdomen. The Cmax was comparable after SC administration in the quadriceps or abdomen, and ~ 17% higher in the gluteus. The absorption was rapid (30 minutes) after administration of the treatment at any site. The treatment was well tolerated. CONCLUSIONS: The relative bioavailability of SC diclofenac HPbCD was comparable when administered to the quadriceps, gluteus, and abdomen. The new diclofenac formulation can therefore be administered subcutaneously to any of these sites without clinically significant differences. A further adequately powered study would be necessary to reveal any differences among injection sites in terms of peak plasma concentration.

Pharmacokinetic characterization of tizanidine nasal spray, a novel intranasal delivery method for the treatment of skeletal muscle spasm.

BACKGROUND AND OBJECTIVE: The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets. METHODS: This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry. RESULTS: There was a linear relationship between different dosages of intranasal formulation and the area under the concentration-time curve and maximum plasma concentration (C(max)). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C(max) values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C(max) (t(max)) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets. CONCLUSIONS: The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t(max) was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II.

Isoflavones: estrogenic activity, biological effect and bioavailability.

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-ß-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.

Human pharmacokinetics of the muscle relaxant, eperisone hydrochloride by liquid chromatography-electrospray tandem mass spectrometry.

Eperisone hydrochloride (4'-ethyl-2-methyl-3-piperidinopropiophenone hydrochloride) is a muscle relaxant agent, widely used in the treatment of patients with muscular contractures, low back pain or spasticity. Because of its mechanism of action (inhibition of gamma-efferent firing and local vasodilatation activity), side effects on central nervous system are rarely observed. A sensitive liquid chromatography-electrospray ionization-mass spectrometry method for determination of eperisone in human plasma has been developed, with a lower limit of quantification of 0.01 ng/mL. The method was applied to a pharmacokinetic study in 12 healthy volunteers given eperisone 100 mg as single dose on day 1 and three times daily on days 2 to 4. Eperisone was rapidly absorbed after oral administration (T (max) = 1.6 h) as it was expected by its fast-onset relaxant activity. Moreover, eperisone underwent a rapid elimination from the body (biological half-life 1.87 h), which was not modified during the repeated dosing as suggested by the C (max) cumulation observed, not different from that expected for a t (1/2) of 1.87 h as suggested by the similar and negligible plasma concentration values (0.063 and 0.067 ng/mL) measured on day 4 before the morning dose and 12 h after evening dose, thus ruling out any potential risk for drug accumulation. Thus, the pharmacokinetic characteristics of eperisone provide further justification for its tolerability in patients with low back pain or spastic palsy, in which the drug is given for periods ranging from few days to several months, respectively.