Can causality assessment fulfill the new European definition of adverse drug reaction? A review of methods used in spontaneous reporting.

Causality assessment is a fundamental biomedical technique for the signal detection performed by Pharmacovigilance centers in a Spontaneous reporting system. Moreover, it is a crucial and important practice for detecting preventable adverse drug reactions. Among different methods for causality assessment, algorithms (such as the Naranjo, or Begaud Methods) seem for their operational procedure and easier applicability one of the most commonly used methods. With the upcoming of the new European Pharmacovigilance legislation including in the definition of the adverse event also effects resulting from abuse, misuse and medication error, all well-known preventable causes of ADRs, there was an emerging need to evaluate whether algorithms could fulfill this new definition. In this review, twenty-two algorithmic methods were identified and none of them seemed to fulfill perfectly the new criteria of adverse event although some of them come close. In fact, several issues were arisen in applying causality assessment algorithms to these new definitions as for example the impossibility to answer the rechallenge question in case of medication error or AEFI (Adverse Event Following Immunization). Moreover, the exact conditions at which events occurred, as for example dosage or mode of administration should be considered to better assess causality in conditions of abuse/overdose, or misuse as well as in conditions of lack of expected efficacy reports for biotechnological drugs and adverse event occurring after mixing of vaccines. Therefore, this review highlights the need of updating algorithmic methods to allow a perfect applicability in all possible clinical scenarios accordingly or not with the terms of marketing authorization.

Drugs approved for the treatment of multiple sclerosis: review of their safety profile.

INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the brain and spinal cord characterized by inflammation, demyelination, and axonal degeneration. Area covered: Even though the pharmacological armamentarium for MS treatment is considerably improved in the last 20 years, safety data especially for the second-line and innovative treatments are lacking. In order to analyze the safety profile of drugs used for the treatment of MS, a literature review of pre-marketing, post-marketing studies and case reports was performed. Expert opinion: Nowadays, the numerous drugs approved in the last years for the treatment of MS allow a better control of the disease and a better patient compliance. The main advantages of the new disease-modifying agents for MS (DMTs), in fact, derive from the new oral administration and the prolonged half-life with consequent improvement in compliance compared to first-line therapy which required subcutaneous administrations. However, DMTs can cause serious, sometimes life-threatening or fatal, drug adverse reactions. Due to the lack of safety data and given the recent marketing approval of the last DMTs for MS, observational studies and post-marketing surveillance activities will be necessary in order to improve the knowledge about the safety profile of these drugs and the improvement of their use in clinical practice.

Campania Preventability Assessment Committee (Italy): A Focus on the Preventability of Non-steroidal Anti-inflammatory Drugs' Adverse Drug Reactions.

Purpose: This study aims to investigate preventability criteria of adverse drug reactions (ADRs) involving non-steroidal anti-inflammatory drugs (NSAIDs) by analyzing individual case safety reports (ICSRs) sent through Campania region (Italy) spontaneous reporting system from July 2012 to October 2016. Methods: For all the ICSRs that reported NSAIDs as suspected drug, a trained multidisciplinary team of Campania Pharmacovigilance Regional Centre composed of clinical pharmacologists and pharmacists with pluriannual experience in Pharmacovigilance assessed preventability by using the P-method. Results: In all 19,039 ICSRs were sent to Campania Pharmacovigilance Regional Centre, of which 550 reported NSAIDs as suspected drug. In total, 94 cases (17.1%) out of 550 ICSRs were preventable. In the 94 preventable cases, 201 critical criteria were detected of which 182/201 (90.5%) related to healthcare professionals' practices, 0/201 (0.0%) to drug quality, and 19/201 (9.5%) to patient behavior. The most detected critical criteria were the necessary medication not given (52/182; 28.6%), labeled drug-drug interaction (36/182; 19.7%), incorrect drug administration duration (31/182; 16.9%), wrong indication (26/182; 14.2%), therapeutic duplication (18/182; 10.0%), and documented hypersensitivity to administered drug or drug class (10/182; 5.6%). In seventeen (18.1%) preventable cases, there were 19 critical criteria involving non-compliance (15/19 critical criteria; 78.9%) and self-medication with the non-over-the-counter drugs (4/19 critical criteria; 21.1%). In all, 17 out 94 (18.1%) preventable cases involved over-the-counter drugs. Conclusion: A call for action for Campania Pharmacovigilance Regional Centre is necessary in order to promote initiatives to increase the awareness of healthcare professionals and citizens on the risk associated with inappropriate use of NSAIDs.

Medication adherence and the use of new pharmaceutical formulations: the case of levothyroxine.

According to World Health Organization, medication adherence refers not only to pharmacological treatment, but also extends to all behaviors which guarantee patient's health. Poor medication adherence is the main cause of low efficacy of pharmacological therapy and it is more common in chronic diseases. For example, among hypothyroid patients, it was estimated that after 5 years of levothyroxine therapy 21.5% of patients still have a TSH level >5.0 mU/L due to poor medication adherence. Moreover, it was found that almost 40% of pediatric patients had at least one episode of non-compliance following thyroidectomia. Several strategies can be adopted in order to improve medication adherence. These include self-monitoring drug therapy and self-management programs, simplified dosing regimens, directly involving pharmacists in drug therapy management, use of pharmaceutical formulations more attractive to the patient and through the therapeutic drug monitoring. The effects mediated by the thyroid gland, the clinical symptoms of hypothyroidism and the main characteristics of levothyroxine therapy have been discussed. In order to give an overview of interactions with food and drinks, pharmacokinetic characteristics, efficacy/safety profile, as well as the impact on medication adherence of levothyroxine in oral solution and soft gel capsule formulations, a literature search was performed. The results of 21 clinical studies were reviewed. Levothyroxine oral solution and soft gel capsule formulations showed irrelevant interactions with food and drinks, with a dissolution profile minimally influenced by pH variations. According to pharmacokinetic study results, bioequivalence between these formulations and levothyroxine tablets was confirmed. Regarding the efficacy/safety profile, while some studies did not detect any difference between levothyroxine formulations, other studies suggested that oral solution and soft gel capsule were associated to a higher efficacy compared to levothyroxine tablet. It was also demonstrated that removing the demand for fasting, patients would prefer to take the medication at breakfast. Therefore, most of the patients treated with levothyroxine oral solution preferred to continue this therapy instead of treatment with tablets. An increase in patient's compliance was observed. All the characteristics of new levothyroxine oral liquid formulations allow to administer the drug also in patients with gastrointestinal comorbidities or patients who are already treated with other drugs. The availability of different dosages let the clinician to adapt the treatment for each individual patient. These benefits contribute to a better medication adherence and to the maintenance of normal TSH levels. In conclusion, the use of different pharmaceutical formulations represents a therapeutic approach innovative, effective and inexpensive in the treatment of the hypothyroid patient.

Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia: A Review of Clinical Cases.

Dipeptidyl peptidase (DPP)-4 inhibitors are a class of oral drugs used for the treatment of type 2 diabetes mellitus (T2DM). The pharmacological inhibition of DPP-4 seems to also induce adverse events related to cytokine-induced inflammation. Recently, several clinical cases regarding the association of DPP-4 inhibitors and the onset of arthritis/arthralgia have been reported in the literature. Various mechanisms could be responsible for DPP-4 inhibitor-induced arthritis/arthralgia, and the increase of cytokines, chemokines, matrix metalloproteinases (MMPs) and genetic factors plays an important role. The US FDA published a safety announcement regarding the entire drug class, encouraging healthcare professionals and patients to pay attention to the occurrence of arthralgia during treatment with DPP-4 inhibitors; arthralgia could be assessed as a class adverse drug event for DPP-4 inhibitors. To summarize the evidence on the correlation between DPP-4 inhibitors and arthritis/arthralgia, and to explain the measures taken by the FDA with regard to arthralgia risk, we performed a literature review of recent evidence concerning this association. This review shows the necessity of other studies to better define the association between DPP-4 inhibitors and arthritis/arthralgia.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

BACKGROUND: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. OBJECTIVES AND METHODS: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-ß-cyclodextrin (HPßCD) and progesterone/HPßCD associations. RESULTS: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPßCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPßCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. CONCLUSIONS: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.

A case of figurate urticaria by etanercept.

Etanercept is a competitive inhibitor of tumor necrosis factor-alpha (TNF-α) a polypeptide hormone, involved in the development of the immune system, in host defense and immune surveillance. Even if the etanercept mechanism of action is not completely understood, it is supposed that it negatively modulates biological responses mediated by molecules (cytokines, adhesion molecules, or proteinases) induced or regulated by TNF. For this reason, it is widely used in the treatment of immunologicals diseases, such as rheumatoid and psoriatic arthritis, polyarticular juvenile idiopathic active, ankylosing spondylitis, and plaque psoriasis. Etanercept has a good tolerability profile. Adverse events related to skin are rare, arising usually in about 5% of patients treated with anti-TNF α. In this scenario, we describe a case of figurate urticaria arose after the re-administration of etanercept in a patient affected by psoriasis and hepatitis B. A 65-year-old man, affected by psoriasis, was hospitalized in September 2014 to the Regional Center for the treatment of psoriasis and Biological Drugs of Second University of Naples for progressive extension of psoriatic skin lesions. The laboratory analysis detected positivity for hepatitis B virus (HBV) antigens. For this reason, it was administered to him lamivudine 100 mg/die about 30 days before to start etanercept treatment. The etanercept therapy has resulted in a progressive improving of skin manifestations, and the patient decided individually to stop the therapy. Afterwards, for worsening of the psoriatic lesions, he was again hospitalized and treated with the same therapeutic schedule (lamivudine followed by etanercept). Ten days after the start of therapy, the patient showed the onset of urticarial rash. Due to this, the treatment with lamivudine and etanercept was suspended and the patient's clinical conditions improved. It is probably that immunological disorders due to etanercept therapy and HBV infection could explain the onset of figurate urticaria in our patient. In this contest, the post-marketing surveillance confirms its important role in the monitoring of drugs tolerability and effectiveness.

Campania preventability assessment committee: a focus on the preventability of the contrast media adverse drug reactions.

OBJECTIVE: The current study aims to assess the preventability of the contrast media adverse drug reactions reported through the Campania spontaneous reporting system, identifying the possible limitations emerged in this type of evaluation. METHOD: All the individual case safety reports validated by the Campania Pharmacovigilance Regional Centre from July 2012 to September 2015 were screened to select those that reported contrast media as suspected drug. Campania Preventability Assessment Committee, in collaboration with clinicians specialized in Radiology, assessed the preventability according to the P-Method, through a case-by-case approach. RESULTS: From July 2012 to September 2015, 13798 cases were inserted by pharmacovigilance managers in the Italian Pharmacovigilance Network database (in the geographical contest of the Campania Region), of which 67 reported contrast media as suspected drug. Five preventable cases were found. The most reported causes for preventability were the inappropriate drug use for the case clinical conditions and the absence of the preventive measure administrated prior to the contrast media administration. Several limitations were found in the evaluation of the critical criteria for the preventability assessment. CONCLUSIONS: Educational initiatives will be organized directly to the healthcare professionals involved in the contrast media administration, to promote an appropriate use of the contrast media.