Current Drug Safety - Volume 8, Issue 3, 2013

Background: Recent evidence suggests that periconceptional folic acid use could not only prevent neural tube defects but also other malformations. The objectives of this study were to assess trends in dispensed high dose periconceptional folic acid (5 mg) and birth prevalence of major congenital malformations. Methods: The Quebec Pregnancy Registry, an administrative database with information on periconceptional prescribed medication and diagnostic codes was used to conduct this study. All pregnant women insured by the Quebec public drug plan between January 1st 1998 and December 31st 2008 were included. The exposure was defined as the use of high dose periconceptional folic acid 30 days before, and during the first 70 days of pregnancy. The outcome measured was the birth prevalence of major congenital malformations among live births. Results: We identified 152,392 pregnancies and babies. The annual prevalence of high dose periconceptional folic acid use increased from 0.17% to 0.80% (p<0.05) during the study period; birth prevalence of congenital malformations increased by 15% (3.35% to 3.87%, p<0.05). More specifically, a 23% increase in the prevalence of cardiac malformation and 23% increase in musculoskeletal defects were observed, whereas there was no change in the prevalence of malformations of the nervous system. Conclusions: Although there was an increase in the use of periconceptional high dose folic acid over the past decade, there was no decrease in the prevalence of major congenital malformations. A limitation of this study is the absence of data on low dose folic acid use, available over the counter, in our administrative database.

Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted information about study design (clinical trials, spontaneous report). Discrepancies in ADR labelling for the medications were found across the three countries. A total of 75 ADR categories were listed for atomoxetine and 80% of these were listed in all three countries. For methylphenidate, totally 101 ADR categories and for modafinil 115 ADR categories were listed. For both substances approximately 60% of listed ADRs were found in all three countries. Discrepancies were primarily detected for ADRs information based on clinical trials. For methylphenidate, many ADRs labelled in Australia and Denmark were not mentioned in PIs issued in the United States. In conclusion, information about possible ADRs associated with the use of a specific product should be made available worldwide, as the prescriber information about medicines’ safety profile should not depend on the country in which the medication is licensed.

This review article systematically and critically summarizes the current evidence regarding desipramine for treating children and adolescents with attention deficit hyperactivity disorder (ADHD). PRISMA guideline was used for gathering the data. The databases of PubMed/Medline and Google scholar were electronically searched. This review included controlled clinical trials investigating the efficacy of desipramine for treating children and adolescents with ADHD. The primary outcome measure was clinical improvement measured by valid and reliable objective instruments in order to assess the severity of ADHD clinical symptoms. Adverse effects were evaluated as well. Out of 267 titles under the study, thirty three articles mentioned desipramine for treating ADHD. Two trials met the inclusion criteria. Desipramine decreases ADHD clinical symptoms. However, there are many concerns about its safety and efficacy. In view of serious concerns about its safety and lack of enough well-controlled trials providing strong evidence about the efficacy of desipraimine, it should be prescribed for treating children with ADHD with a high precaution, and further well-controlled trials should be performed.

Objective: Hyponatraemia is a serious adverse event commonly reported in elderly people treated with serotonergic antidepressants. The mechanism, incidence and risk factors for antidepressant induced hyponatraemia are not fully understood. Method: In a retrospective chart analysis, depressed patients aged >63 years were investigated for change in serum sodium levels between two time points, separated by a median period of 45.5 days, with the first specimen taken prior to treatment. Patients were grouped into three cohorts; treated with an SSRI or SNRI (n=77), treated with an antidepressant other than an SSRI or SNRI (n=54) and not treated with an antidepressant (n=128). Results: For change in sodium level between measurements and total number of patients with hyponatraemia, there was no significant difference between cohorts. However, the rate of reduction of serum sodium levels between time points was significantly greater for SSRI and SNRI treated patients (p<0.001) and patients treated with other antidepressants (p=0.03) compared to patients not treated with antidepressants. Moreover, the distribution of values of change in serum sodium was skewed towards reduced serum sodium in patients treated with SSRI or SNRIs (skew -0.43) and patients treated with other antidepressants (skew -0.09) but not for patients without antidepressants (skew 0.25). Conclusions: These data suggest that antidepressant treatment is associated with hyponatraemia affecting a subgroup of individuals only. Generalised linear modelling showed that the risk of hyponatraemia increases with increased age, female gender, and particularly the antidepressant agents sertraline and escitalopram. The findings are of clinical significance as they demonstrate that hyponatraemia can occur rapidly with antidepressants, and SSRI/SNRI medications induce more rapid changes. They support the use of electrolyte monitoring early in antidepressant treatment in patients receiving antidepressants.

Purpose: Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE. Methods: A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed. Results: Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE. Conclusions: Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.

Context and Aim: Asthma is a common problem in paediatric population. International treatment guidelines recognize the role of inhaled corticosteroids for asthma in young children. Inhaled fluticasone propionate is reported to have greater systemic effects like other corticosteroids. Limited data is available on safety of this drug when used for longer duration. So, we conducted a systematic review to study the effect of inhaled fluticasone propionate on adrenal suppression, growth and bone mineral density in paediatric patients. Design: A systematic review Methods: We searched for Randomized controlled trials in MEDLINE from January 2000 to December 2012. References of included study were hand searched. Information on study design, study population, drugs and dosage used, follow up period, measures used to evaluate safety and outcomes was abstracted independently by three reviewers. Details of Included Studies: In all included studies, participants were asthmatic children below 18 years and treated with fluticasone propionate. Minimum follow up considered was three months and should have measured HPA suppression or growth velocity or bone mineral density. Results: Total ten studies were included. Studies which had monitored HPA function varied in dosage of drug, mode of administration and duration. Inspite of that it has been observed that serum cortisol level is affected by fluticasone propionate, no significant effect on bone mineral density was reported with fluticasone propionate, but the sample size was inadequate and dietary calcium intake was not recorded. None of the studies reported any significant reduction in growth when inhaled fluticasone propionate was used for the treatment of asthma, but the baseline growth and final adult height attained were not assessed. Limitation: This systematic review included only free full text articles published in English. Only randomized controlled trials were included. Cohort studies were not included. Conclusion: With available evidences, the safety of inhaled fluticasone propionate cannot be questioned. This systematic review could not derive any significant adverse effect on HPA function, growth and bone mineral density in asthmatic children when used for long duration and followed for up to three months.

The standard version of the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster was employed in order to evaluate the genotoxic potential of metronidazole (MTZ) as a function of exposure concentration. MTZ was administered by chronic feeding of 3-day-old larvae with the parenteral solution at 0, 500, 1000 and 2000 µg/ml until pupation. The marker-heterozygous progeny (mwh+/+flr3) with phenotypically wild-type wings was analyzed. Non significant differences were found between control and each MTZ concentration tested for single small spots (SSS) frequencies. Large single spots (LSS) and twin spots (TS) were significantly increased with the higher dose. MTZ treatments with 1000 and 2000 µg/ml also significantly increased the frequency of Total spots. These findings suggest that MTZ is genotoxic in the present experimental conditions and induces recombinagenesis and/or gene conversion, two major mechanisms that cause loss of heterocigosity and could play an important role in tumorigenesis and carcinogenesis processes.

Levofloxacin induced psychiatric adverse effects are rare, although they can be serious. There are just five cases of fluoroquinolone-induced delirium published in the medical literature. To our best knowledge, none of them occurred in psychotic patients. We report a case of a 38-year-old Caucasian man diagnosed with schizoaffective disorder and multiple sclerosis who developed delirium and visual hallucinations after initiating levofloxacin therapy. In psychiatric patients, suspecting levofloxacin could be responsible for the symptoms can be a diagnostic challenge, since they could be interpreted like worsening of the mental state as well. Although levofloxacin-induced delirium is a rare adverse event, physicians should be aware of the occurrence of this serious, but potentially reversible CNS complication of levofloxacin, even in psychotic patients.

Dronedarone was introduced in 2009 as a new antiarrhythmic agent and since then has been increasingly prescribed in atrial fibrillation or flutter. To date, two cases of severe toxic hepatitis have been reported in patients treated with dronedarone, both requiring emergency liver transplantation, and the FDA as well as the EMA have issued warnings about possible severe hepatotoxicity of dronedarone. Here we report an additional case of toxic hepatitis associated with dronedarone presenting with acute liver failure, followed by spontaneous recovery, in a 69-year old woman.

Immediate management of drug overdose relies upon the patient account of what was ingested and how much. Paracetamol (acetaminophen) is involved in around 40% of intentional overdose episodes, and remains the leading cause of acute liver failure in many countries including the United Kingdom. In recent years, consumers have had increasing access to medications supplied by international retailers via the internet, which may have different proprietary or generic names than in the country of purchase. We describe a patient that presented to hospital after intentional overdose involving ‘acetaminophen’ purchased via the internet. The patient had difficulty recalling the drug name, which was inadvertently attributed to ‘Advil’, a proprietary non-steroidal anti-inflammatory drug. The error was later recognised when the drug packaging became available, but the diagnosis of paracetamol overdose and initiation of acetylcysteine antidote were delayed. This case illustrates the benefit of routinely measuring paracetamol concentrations in all patients with suspected poisoning, although this is not universally accepted in practice. Moreover, it highlights the importance of the internet as a source of medications for intentional overdose, and emphasises the need for harmonisation of international drug names to improve patient safety.

Antidepressants are commonly prescribed and used in the management of depression, anxiety disorders, and other psychiatric illnesses. Antidepressants used in therapeutic dosing ranges are associated with causing several adverse drug reactions including hepatotoxicity. Paroxetine, fluoxetine, fluvoxamine, citalopram, mirtazapine and venlafaxine are associated with reversible liver injury upon discontinuation of the agent. Patient cases of hepatotoxicity involving the use of nefazodone, trazodone, duloxetine, bupropion, and sertraline are linked to causing death in its users. Due to the idiosyncratic nature of hepatotoxicity, monitoring of liver function tests and immediate discontinuation upon abnormal lab findings or signs and symptoms of liver dysfunction are crucial since most cases of hepatic damage are reversible when detected early. Onset of antidepressant-associated hepatotoxicity varies from 5 days to 3 years. Antidepressant-induced liver injury can occur in the absence of identifiable, underlying risk factors such as cirrhosis and hepatitis infection; only a few cases of hepatic injury involve patients with chronic hepatitis infection. Some of these cases involve possible drug interactions between antidepressants and concomitant agents that increase the risk for liver injury. Understanding druginduced liver injury associated with antidepressants and the importance of safety monitoring is essential to optimize outcomes for antidepressant treatment.