Drug Safety

Correction to: Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists In the original publication of this article, the following correction should be noted in Table 1.

A Profile of Adverse Drug Reactions of Atazanavir- and Lopinavir-Based Antiretroviral Regimens in Namibia

Inflammation, Monoclonal Antibodies and Depression: Joining the Dots

Sirolimus and mTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation Abstract Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to mechanisms hypothesized to cause adverse events and their management strategies.

Drug-Induced Photosensitivity—An Update: Culprit Drugs, Prevention and Management Abstract Photosensitive drug eruptions are cutaneous adverse events due to exposure to a medication and either ultraviolet or visible radiation. In this review, the diagnosis, prevention and management of drug-induced photosensitivity is discussed. Diagnosis is based largely on the history of drug intake and the appearance of the eruption primarily affecting sun-exposed areas of the skin. This diagnosis can also be aided by tools such as phototesting, photopatch testing and rechallenge testing. The mainstay of management is prevention, including informing patients of the possibility of increased photosensitivity as well as the use of appropriate sun protective measures. Once a photosensitivity reaction has occurred, it may be necessary to discontinue the culprit medication and treat the reaction with corticosteroids. For certain medications, long-term surveillance may be indicated because of a higher risk of developing melanoma or squamous cell carcinoma at sites of earlier photosensitivity reactions. A large number of medications have been implicated as causes of photosensitivity, many with convincing clinical and scientific supporting evidence. We review the medical literature regarding the evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing. Amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib and voriconazole are among the most consistently implicated and warrant the most precaution by both the physician and patient.

Exploring the Association between Monoclonal Antibodies and Depression and Suicidal Ideation and Behavior: A VigiBase Study Abstract Introduction Several monoclonal antibodies (mAbs) have been linked to neuropsychiatric adverse effects in patients, including depression and suicidal ideation and behavior. Objective The aim of this study was to quantify and characterize spontaneously reported adverse drug reactions (ADRs) of depression and suicidal ideation and behavior related to mAb users, and to explore a possible association with their mechanism of action. Methods We included mAb ADRs that were reported in VigiBase, and identified those related to depression and suicidal ideation and behavior. Reporting odds ratios (RORs) were estimated for each mAb (bevacizumab as the reference) and according to their influence on the immune system (not directly targeting [reference], stimulating, or suppressing). Those suppressing the immune system were further divided into their intended indication (auto-immune diseases, cancer). Results Overall, 2,924,319 ADRs for 44 mAbs were included; 9455 ADRs were related to depression and 1770 were related to suicidal ideation and behavior. The association was strongest for natalizumab and belimumab, both for depression (ROR 5.7, 95% confidence interval [CI] 5.0–6.4; and ROR 5.1, 95% CI 4.2–6.2) and suicidal ideation and behavior (ROR 12.0, 95% CI 7.9–18.3; and ROR 20.2, 95% CI 12.4–33.0). Those suppressing the immune system showed higher ROR, i.e. 1.9 (95% CI 1.8–2.0) for depression and 3.6 (95% CI 3.0–4.4) for suicidal ideation and behavior. This finding was only seen for mAbs used for treating autoimmune diseases. Conclusion Depression and suicidal ideation and behavior are seen in patients using mAbs, particularly mAbs used for treating autoimmune diseases that suppress the immune system. For interpretation of these data, the indications for use and other characteristics require further consideration.

Long-Term Safety and Efficacy of Fecal Microbiota Transplant in Active Ulcerative Colitis Abstract Introduction and objective The therapeutic role of fecal microbiota transplantation in ulcerative colitis varies across different reports. This study aims to evaluate the long-term safety and efficacy of a strategy called step-up fecal microbiota transplantation for ulcerative colitis. Methods Two clinical trials (NCT01790061, NCT02560727) for moderate-to-severe ulcerative colitis (Mayo score range 6–12) were performed from November 2012 to July 2017. Both studies were pooled for analysis on the safety and efficacy of fecal microbiota transplantation in patients with ulcerative colitis over a 1-year follow-up. The step-up fecal microbiota transplantation strategy included step 1: single fecal microbiota transplantation; step 2: two or more fecal microbiota transplantations; and step 3: fecal microbiota transplantations followed by immunosuppressants. Long-term clinical efficacy and adverse events were assessed, and multiple factors related to fecal microbiota transplantation were evaluated. Results Of 134 eligible patients in this real-word study, 81.3% (109/134) were included for analysis. The follow-up ranged from 1 to 5 years. Fecal microbiota transplantation-related adverse events were observed in 17.4% (43/247) of fecal microbiota transplantation procedures including one serious adverse event (myasthenia gravis) and 56 non-serious adverse events. Multivariable logistic regression analysis showed that both the method of preparation of microbiota from stool using the automatic system and the delivery method of colonic transendoscopic enteral tubing were associated with a lower rate of fecal microbiota transplantation-related adverse events (p = 0.023, p = 0.017, respectively). In total, 74.3% (81/109) and 51.4% (56/109) of patients achieved clinical response at 1 month and 3 months after step-up fecal microbiota transplantation, respectively. Conclusions Fecal microbiota transplantation should be a safe and promising therapy for ulcerative colitis. The improved fecal microbiota preparation and colonic transendoscopic enteral tubing might reduce the rate of adverse events in ulcerative colitis. Trial registration ClinicalTrials.gov NCT01790061, NCT02560727.

Summary of Torsades de Pointes (TdP) Reports Associated with Intravenous Drug Formulations Containing the Preservative Chlorobutanol Abstract Introduction Drug-induced torsades de pointes (TdP) is a potentially lethal ventricular arrhythmia that is associated with drugs that prolong the QT interval on the electrocardiogram (ECG) due to their interference with the cardiac potassium current, IKR. Intravenous (IV) formulations of methadone have been associated with TdP and contain the preservative chlorobutanol, which, like methadone, blocks IKR. The combinations of chlorobutanol with methadone or terfenadine, another IKR blocker, produce synergistic IKR block. Objective The aim of this study was to examine and summarize the evidence available to address the question: what other IV drug formulations contain chlorobutanol and are they associated with TdP? Methods IV drug products containing the preservative chlorobutanol were identified by searching the websites DailyMed (https://dailymed.nlm.nih.gov/dailymed/index.cfm) and Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/). For each drug identified, PubMed and the FDA's Adverse Event Reporting System (FAERS) were searched for reports of TdP and/or QT prolongation and FAERS data were analyzed for disproportionality of reports. Results The search found nine drugs (methadone, epinephrine, papaverine, oxytocin, vasopressin, testosterone, estradiol, isoniazid, and desmopressin) that contain chlorobutanol 2.5 (n = 1) or 5.0 mg/mL. All nine drugs had reports of QT prolongation or TdP reported in FAERS and all but estradiol, testosterone, desmopressin, and isoniazid had reports of QT prolongation or TdP in PubMed. Two of the nine drugs (epinephrine and methadone) had positive signals (by disproportionality analysis) for TdP in FAERS (EB05 2.88 and 23.81, respectively) and four (methadone, epinephrine, papaverine, and vasopressin) were reported in published articles as the suspect drugs in cases of TdP. Conclusion The pharmacologic profile of chlorobutanol (synergistic IKR block) and its association with reports of TdP and QT prolongation suggest the need for a full evaluation of its cardiac safety when used as a preservative in IV drug and vitamin formulations.

Pharmacovigilance Systems in Arab Countries: Overview of 22 Arab Countries Abstract Pharmacovigilance has received much attention in Arab countries recently due to the development of new regulations. However, there are differences in the progression of pharmacovigilance systems by regulatory agencies in these countries because only some are able to meet the requirements for conducting pharmacovigilance activities. Only 45% of Arab countries are official members of the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring. Countries such as Morocco, Tunisia, Saudi Arabia, Egypt, and Jordan are considered to be advanced pharmacovigilance countries, whereas other countries such as Libya, Yemen, and Palestine remain in the very early stages of implementing and developing pharmacovigilance systems. Countries such as Somalia, Djibouti, Mauritania, and Comoros Island have no pharmacovigilance system or culture. Asian Arab countries have some advantages over those in Africa because 50% of them are a part of the Gulf Cooperation Council (GCC), meaning that most of them can utilize similar approaches for the application of the majority of activities related to the healthcare system, including pharmacovigilance. Thus, participating in the GCC enables increased connections among these countries. However, one of the strengths in Africa is that Morocco is partnering with the WHO through the WHO Collaborating Center to enhance and strengthen pharmacovigilance across the Eastern Mediterranean Region and the Francophone and Arab countries. This partnership could have a role in enhancing the pharmacovigilance culture among African Arab countries. This review provides a general overview of the current situation regarding regulatory agencies related to pharmacovigilance in Arab countries.

Use of FDA's Sentinel System to Quantify Seizure Risk Immediately Following New Ranolazine Exposure Abstract Introduction Neurological complications including seizures have been reported with ranolazine. We sought to quantify the risk of seizure-related hospitalizations or emergency department events following ranolazine exposure in the Sentinel System (2006–2015). Study Design and Setting Eligibility criteria were new use of ranolazine after 183 days washout period and absence of seizure diagnoses, anti-epileptic drugs, or seizure-related disorders during the baseline period. Results Among 52,155 ranolazine users, we identified 28 seizures in the 1–32 days after new ranolazine dispensing: 12 occurring in days 1–10 (high-risk window), 11 in days 11–20 (moderate-risk window) and 5 in the control window (days 21–32). Assuming an equal likelihood of seizure events across the 32-day observation window, we estimate an attributable risk of 0.9 excess cases per 10,000 exposed users. Using a self-controlled risk interval design with exact logistic regression, seizures were elevated in the high-risk window (relative risk [RR] 2.88 (95% confidence interval [CI] 1.01–8.33) compared with the control window. No significant increased risk was observed in the moderate window. Half of the seizure cases had a diagnosis of renal disease, although seizure risk was not significant (RR 3.20 [CI 0.82–14.01]). A majority of patients in both risk windows were 75 years or older. Conclusion Our study suggests risk among younger ranolazine patients is rare. Given the imprecision of the risk estimates, we interpret the elevated seizure risk following ranolazine exposure with caution. Further analysis in a larger elderly population is warranted.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com