Current Drug Safety - Volume 14, Issue 1, 2019

Background: Intravenous Immunoglobulin (IVIg) forms a cornerstone of effective treatment for acute and chronic inflammatory neuropathies, with a class I evidence base in Guillain-Barré Syndrome (GBS), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). It is generally considered to be a safe therapy however there are several recognised complications which are reviewed in this article. Discussion and Conclusion: Most adverse events are immediate and mild such as headache, fever and nausea although more serious immediate reactions such as anaphylaxis may rarely occur. Delayed complications are rare but may be serious, including thromboembolic events and acute kidney injury, and these and associated risk factors are also discussed. We emphasise the importance of safe IVIg administration and highlight practical measures to minimise complications of this therapy.

Background: The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunomodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin. Objective: To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management. Method: English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review. Results: The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life-threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported. Conclusion: Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment so that permanent discontinuation of therapy is not commonly necessary. In the case of life-threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

Background: The signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously”. Objective: To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). Methodology: The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. Results: The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. Conclusion: Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

Background: Cardioselective beta-blockers may affect glucose or lipid profiles. Objective: We sought to compare the effects of two beta-blockers, metoprolol and bisoprolol, as the most commonly used drugs in cardiology, on glucose and lipid profiles in patients with cardiovascular diseases. Methods: We conducted a retrospective cross-sectional matched study at Prince Sultan Cardiac Center in Burydah in August 2017. Patient records were screened, and adult patients with cardiovascular disorders who were treated with a stable dose of metoprolol or bisoprolol were included. Parameters related to glucose and lipid metabolism were compared using the Student's t-test between the two groups. Results and Conclusion: The metoprolol and bisoprolol arms included 204 and 200 patients, respectively.

Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

Background: Dapsone is a sulfone derived drug used in the treatment of leprosy and several chronic inflammatory dermatological diseases. Dapsone Hypersensitivity Syndrome (DHS) is characterized by fever, hepatitis, generalized exfoliative dermatitis and lymphadenopathy. It is rare and potentially fatal. Case Report: We present a case report of a 52 years old female with a recent history of antecedent dapsone exposure of 100 mg daily for 2 weeks. She developed fever 10 days after exposure to dapsone therapy and was treated in various primary and tertiary centers for features of sepsis. When she presented to us, clinical features of multi-organ dysfunction and intractable sepsis was evident. She was successfully managed with intravenous corticosteroids and other supportive therapy. This case of DHS is unique due to pulmonary, hepatic and colonic involvement in addition to secondary bacterial and fungal infection, which is associated with an increased risk of mortality. Conclusion: As dapsone is mainstay in the treatment several infections and inflammatory conditions, further research is needed to characterize markers to diagnose DHS and to develop screening policies prior to initiation of dapsone therapy.

Introduction: The widespread use of direct oral anticoagulants (DOACs) has been increasing the conditions in which emergency physicians are forced to rapidly reverse anticoagulation in case of life-threatening bleeding or need of urgent surgery or invasive procedures. The recent approval of Idarucizumab, a humanized monoclonal antibody fragment (Fab), offered the opportunity to rapidly and safely neutralize the anticoagulant effect of Dabigatran. However, real-world experience of its effective use in different emergency setting is now required. Lumbar Puncture (LP) is recognized as an invasive procedure at major bleeding risk and is, therefore, contraindicated in anticoagulated patients. Conclusion: We report a successful use of Idarucizumab in an emergency LP of a young woman with a possible diagnosis of encephalitis and a previous history of venous thromboembolism on long-term treatment with Dabigatran 150 mg twice a day.

Purpose: To report a case of a 73-year-old man who presented with decreased visual acuity due to bilateral macular edema after paclitaxel administration for prostate cancer. Methods: The ophthalmic evaluation consisted of medical and ocular history, Best Corrected Visual Acuity, slit-lamp biomicroscopy and Spectral-domain optical coherence tomography / Fluorescein Angiography. Results: Optical Coherence Tomography and Fluorescein Angiography revealed silent cystoid macular edema. After consulting with the oncologist, the cessation of paclitaxel therapy was decided. The patient presented a gradual but steady resumption of the retinal edema, with complete restoration of normal retinal morphology and function within two months. The pathogenesis of the silent Cystoid Macular Edema (CME) is still unclear. Based on our case and a critical review of the previous observations and published data, we propose that the underlying cause of Taxane induced CME is the functional failure of Aquaporin mediated water transport at the level of retinal Intermediate and Deep capillary plexuses, and at lesser extent at the level of the Retinal Pigment Epithelium. Conclusion: Taxane induced silent CME should be attributed to the action of Taxanes on the microtubule guided aquaporin vesicles transport to the cell membrane. In our case of Taxane induced silent CME, withdrawal of the taxane was enough for complete recovery, and no additional treatment was needed.

Objective: Extrapyramidal adverse effects of antipsychotic drugs are more reported in children. Biperiden is an anticholinergic agent to treat the adverse effects of antipsychotic drugs. The drug has the potential to induce delirium at toxic doses. However, data are scarce about delirium associated with biperiden in children. Thus far, a case of delirium has been associated with biperiden in an adolescent patient. We report the first case of delirium associated with the use of biperiden in a preadolescent patient. Case Report: A boy aged five years and weighing 20 kilograms had been diagnosed as having oppositional defiant disorder and separation anxiety disorder in the previous treatment center. Ten milligrams fluoxetine and 0.25 milligrams risperidone had been initiated. On the third day of treatment, dystonia developed and he was administered with biperiden. An hour later, he was brought to our emergency clinic due to disorganized speech and behavior. His vital signs were stable. There were no findings in blood and urine tests. No electrolyte imbalance, liver, kidney, and thyroid dysfunction have been observed. His neurologic examination was unremarkable and no abnormal findings were shown on cranial magnetic resonance imaging. No other system findings or findings pointing out to infectious diseases have been observed. One milligram physostigmine was administered with intravenous infusion. However, symptoms did not resolve and he was diagnosed with delirium. Naranjo Adverse Drug Reaction Probability Scale score was seven, indicating a “Probable” Adverse Drug Reaction. Half milligram haloperidol was administered bid for three days and he was discharged with complete recovery. Conclusion: Clinicians must be aware of the risk of delirium when using non-toxic doses of biperiden in young children.

Background: Dyskinetic neurological diseases are common presentations of adverse reaction to many therapeutic agents. Phenytoin, a widely used age-old antiepileptic drug has been reported to cause dyskinesias, a rare Adverse Drug Reaction (ADR) in adults with toxic therapeutic serum level. When the drug is used in combination with other drugs which augments free drug level of phenytoin or in patients of organic brain lesion, this side effect is very occasionally reported with even normal therapeutic drug level. Clinical Case: We report a case of young male presented with chorea after two months of starting phenytoin for primary generalised epilepsy with normal therapeutic serum drug level. After excluding other differentials, drug-induced chorea was the final diagnosis. Despite phenytoin level was in therapeutic range, we have a trial of stopping Phenytoin with complete disappearance of chorea in 3 days. On reintroduction of phenytoin in the same dose, there was the reappearance of chorea in onemonth re-emphasising the diagnosis as “phenytoin-induced chorea”. Conclusion: If any patient on phenytoin develops any new neurological feature including dyskinesias, it should be considered as an ADR despite drug serum level within the normal therapeutic range.

Background: The Colombian National Food and Drug Surveillance Institute (INVIMA) is responsible for monitoring the safety and efficacy of medicines circulating the Colombian market. Discussion: This article summarizes the three key strategies the institution has implemented to strengthen the National Pharmacovigilance Program: improving the interaction and working relationship with regional health authorities, expanding the National Pharmacovigilance Network and implementing the electronic submission of adverse events. Conclusion: The number of adverse events reported in Colombia increased from 5,447 in 2013 to 95,658 in 2017, reaching a population-based reporting ratio within international standards (563 in 2016).

Background: Adverse cardiorespiratory events are associated with midazolam continuous IV infusion, used for sedation. History: Here we are reporting a case of 5 year old male child suffering from diphtheria induced airway obstruction, and myocarditis, who received midazolam in the form of IV infusion for sedation while undergoing mechanical ventilation for respiratory failure. Adverse Event: Six hours after starting midazolam infusion he started developing pulsus bigeminus and bradycardia and eventual death after two hours. Conclusion: Midazolam, although considered one of the safest drugs, need to be used cautiously in a child with myocarditis, because of the possible cardiotoxic effect in an already affected heart.

Background: In recent years, few cases of post-artemisinin delayed hemolysis have been reported. Objective: All cases of post-artemisinin delayed hemolysis were reported from non-middle east areas. No case of post-artemisinin delayed hemolysis has yet been reported from this region. In this paper, we describe a case of post-artemisinin delayed hemolysis in an Iranian female. Moreover, previous reports have been reviewed. Methods: Patient's data including demographic characteristics, past medical, drug and travelling history, present illness, vital signs, laboratory data, clinical course of current illness and follow-up findings were considered. Results: A 27-year-old female with a recent travel history to Ghana admitted with severe falciparum malaria. She was successfully treated with parenteral artesunate. However after 12 days of post artesunate treatment, she returned with dark urine, malaise and fatigue. Conclusion: Considering the clinical course and base on a reliable causality assessment scale, post artesunate delay hemolytic anemia was possible.

Background: Direct-acting Antivirals (DAA) are currently used in the treatment of chronic HCV infection. In patients with renal failure Glecaprevir/Pibrentasvir (genotype 1-6) is recommended for its safety and efficacy. Case Presentation: Although these pharmacological characteristics, an adverse drug reaction (ADR) has been reported during Glecaprevir/Pibrentasvir treatment, such as the development of cholestatic jaundice in an elderly patient with chronic HCV (genotype 2) infection. At examination, patient was jaundiced associated with intense pruritus. Results: Ultrasound and laboratory biochemical tests excluded a liver failure (e.g. liver cancer, and liver lithiasis) or pancreatic cancer while Naranjo probability scale (score 6) suggested an association between cholestatic jaundice and Glecaprevir/Pibrentasvir administration. About 1 month after drug discontinuation, an improvement has been documented in both jaundice and pruritus, with a normalization in bilirubin levels (total bilirubin: 0.96 mg/dL), HCV-RNA was undetected also. It is worth mentioning that although we reported the development of cholestatic jaundice upon treatment with Glecaprevir/Pibrentasvir we recorded a clinical efficacy (HCV-RNA <15 IU/L) after 4 weeks from the beginning of the treatment, with a complete remission of clinical symptoms until 7 months after drug discontinuation. Conclusion: These data support the clinical efficacy of Glecaprevir/Pibrentasvir association in elderly patients, despite the sub-optimal period of treatment.

Background: Fixed drug eruption is a clinical entity occurring at the same site each time the drug is administered. They are usually found on lips, genitalia, abdomen, and legs but can occur at any location. The eruptions usually occur within hours of administration of the drug and resolves spontaneously. Most common drugs causing them include antimicrobials. Fluroquinolones especially norfloxacin is commonly used in the treatment of gastrointestinal infections. Cutaneous adverse drug reactions are very rare with norfloxacin. Case Report: In this case report, a young female, soon after taking Nofloxacin tablet, developed a blister with erythema and itching after self treatment for urinary tract infection. It got cured after stopping the drug and taking treatment from a dermatologist. It resolved as a hyper-pigmented scar. She experienced a similar episode of drug eruption on the same site when she again self medicated herself with Norfloxacin for diarrhoea. This time the reaction occurred within few hours and resolved with hyperpigmentation after medication. She was advised not to indulge in self-treatment in future. Suspecting association between the drug and the rash was confirmed and a diagnosis of Norfloxacin induced fixed drug eruption was made. Conclusion: Causality assessment by Naranjo's algorithm revealed a definite relationship between the cutaneous adverse drug reaction and the offending drug.

Background: Psoriasis is a chronic inflammatory skin disorder that may be initiated or exacerbated by some drug intakes. Some of the most common medications known to trigger or worsen existing psoriasis include lithium, gold salts, beta blockers and antimalarials. Conclusion: We report an exceptional case of plantar psoriasis in a woman who was treated by olmesartan for 3 years.

Background: The clozapine-derivative quetiapine has been shown in some cases to cause leukopenia and neutropenia. Case Presentation: We reported on a case of a young female diagnosed with treatment-resistant schizophrenia. After failed trials of three antipsychotic medications and despite a history of quetiapineinduced leukopenia, clozapine treatment was introduced due to the severity of the patient's symptoms, the limited effective treatment options, and a lack of guidelines on this issue. Result: Over a ten-week period of clozapine treatment at 700 mg per day, the patient developed agranulocytosis. Her white blood cell count sharply dropped to 1.6 10⁹ L, and her neutrophils decreased to 0.1 10⁹ L. There had been no similar reaction to her previous medications (carbamazepine, risperidone, and haloperidol). Conclusion: The safety of clozapine in a patient who has previously experienced leukopenia and neutropenia with quetiapine requires further investigation. Increased attention should be paid to such cases. Careful monitoring and slow titration are advisable.