Drug Safety

Pelargonium (Pelargonium sidoides DC and P. reniforme Curtis) is reported to have immune modulating properties and antibacterial activity, and Pelargonium extracts have been used for the treatment of respiratory tract and gastrointestinal infections. Introduced in the early 1980s in Germany, Umckaloabo® (ISO Arzneimittel), an ethanolic extract of the roots of P. sidoides and P. reniforme, was the first Pelargonium- derived product to be commonly used in a country in the EU. According to the Umckaloabo® product information, this extract has no known adverse effects. However, there is a theoretical risk of interactions with anticoagulants such as warfarin, and antiplatelet drugs, such as aspirin (acetylsalicylic acid). To date, the Uppsala Monitoring Centre has, through the WHO international pharmacovigilance programme, received 34 case reports of allergic reactions suspected to be associated with the use of Pelargonium extract, all originating from Germany. In a number of these reports, the description and timing of the event was indicative of an acute Coombs and Gell Type I hypersensitivity reaction; two of these patients needed treatment for circulatory failure. So far, the experience of such reactions is limited to Germany. Since Pelargonium- containing herbal products have recently been approved in a number of other countries, the possibility of the occurrence of allergic reactions has become of more general interest and further information regarding these products is needed.

Irinotecan exerts its cytotoxic activity through inhibition of the nuclear enzyme topoisomerase I. It has been approved in most countries worldwide for treatment of patients with advanced colorectal cancer (CRC). Activity is seen in previously untreated patients and in patients refractory to fluorouracil treatment, whether it is given alone or in combination with other cytotoxic drugs. Irinotecan was first developed in patients refractory to fluorouracil. Activity in terms of tumour responses and patient benefit was seen in several phase II trials that used either a weekly or a three-weekly schedule. In two randomised trials (irinotecan vs best supportive care, and irinotecan vs an infused fluorouracil-based regimen), irinotecan prolonged median survival by approximately 2.5 months without any deterioration in quality-of-life. It was later studied in previously untreated patients with advanced CRC in combination with fluorouracil/folinic acid (leucovorin). In three large randomised trials, median time to tumour progression was prolonged by approximately 2.5 months and overall survival by about 2.5 months compared with fluorouracil/folinic acid alone. Tumour responses were also seen more frequently in the irinotecan arm (35–40% vs 20%). Again, quality-of-life scores were not deteriorated by the addition of irinotecan. Irinotecan has many acute adverse effects. The most prominent and dose limiting being diarrhoea and neutropenia. With irinotecan monotherapy, diarrhoea was seen in 80% of patients and severe grade 3 to 4 diarrhoea occurred in 30–40% of the patients. The severity of diarrhoea can be diminished by preventive actions. Less risk of diarrhoea is generally seen when irinotecan is combined with fluorouracil. Neutropenia is generally short-lived, but may be severe if diarrhoea is also present. This has been noticed particularly when irinotecan has been given in combination with a bolus fluorouracil/folinic acid regimen. Other toxicities include acute cholinergic-like symptoms, nausea and vomiting, and alopecia. In spite of these adverse effects, irinotecan has been accepted as an important first-line treatment for patients with advanced CRC, in combination with, preferably, an infused fluorouracil-based regimen, and has been approved for use as monotherapy in the second-line indication.

Maternal and fetal arrhythmias occurring during pregnancy may jeopardise the life of the mother and the fetus. When arrhythmias are well tolerated and patients are minimally symptomatic, conservative therapy, such as observation and rest or vagal manoeuvres, should be employed. When arrhythmias cause debilitating symptoms or haemodynamic compromise, antiarrhythmic drug therapy is indicated. Although no antiarrhythmic drug is completely safe during pregnancy, most are well tolerated and can be given with relatively low risk. Physiological changes that occur during pregnancy mandate caution when administering antiarrhythmic drugs, with close monitoring of serum concentration and patient response. Drug therapy should be avoided during the first trimester of pregnancy if possible, and drugs with the longest record of safety should be used as first-line therapy. Several therapeutic options exist for most arrhythmias in the mother and fetus. Of the class IA agents, quinidine has the longest record of safety during pregnancy, and is generally well tolerated. Procainamide is also well tolerated, and should be a first line option for acute treatment of undiagnosed wide complex tachycardia. All IA agents should be administered in the hospital under cardiac monitoring due to the potential risk of ventricular arrhythmias (torsade de pointes). The IB agent, lidocaine (lignocaine), has local anaesthetic role but is also generally well tolerated as an antiarrhythmic agents. Phenytoin should be avoided due to the high risk of congenital malformations and limited role as an antiar-rhythmic drug. Of the IC agents, flecainide has been shown to be very effective in treating fetal supraventricular tachycardia complicated by hydrops. β-Blockers are generally well tolerated and can be used with relative safety in pregnancy, although recent data suggest that they may cause intrauterine growth retardation if they are administered during the first trimester. Amiodarone, a class II agents with characteristics of the other antiarrhythmic drug classes, has been reported to cause congenital abnormalities; it should be avoided during the first trimester and used only to treat life-threatening arrhythmias that fail to respond to other therapies. Adenosine is generally safe to use in pregnancy, and is the drug of choice for acute termination of maternal supraventricular tachycardia. Digoxin has a long track record of treating both maternal and fetal arrhythmias, and is one of the safest antiarrhythmics to use during pregnancy. Direct current cardioversion to terminate maternal arrhythmias is well tolerated and effective, and should not be delayed if indicated. The use of an implantable cardioverter-defibrillator should be considered for women of childbearing potential with life-threatening ventricular arrhythmias.

Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

Background: Available evidence indicates that the use of antipsychotics, especially second-generation antipsychotics (SGAs), for children with mental health disorders has increased dramatically. Given the demonstrated metabolic and neurological adverse effects seen in adult patients on these medications, detailed evaluation of the risk for these adverse effects in children is appropriate. Objective: The aim of the study was to assess the evidence for specific metabolic and neurological adverse effects associated with the use of SGAs in children. Data Sources: MEDLINE (1996–May 2010) and EMBASE (1996–May 2010) databases were searched using highly sensitive search strategies for clinical trials in a paediatric population (children up to age 18 years). Study Selection: We included any double-blind, randomized controlled trial (RCT) of SGA medications conducted specifically in a paediatric population for the treatment of a mental health disorder. This included the medications risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone and paliperidone. The primary outcomes assessed for this review were metabolic and neurological adverse effects, as measured using physical examination manoeuvres, rating scales or laboratory tests. A total of 35 RCTs were included in the analysis, but not all studies had data that could be used in the meta-analysis. Data Extraction: Abstracts retrieved from the searches were reviewed independently by two different reviewers for potential relevant articles. Full-text articles were then read in detail independently by two different reviewers to see if inclusion criteria were fulfilled. Data were extracted independently by two review authors from included studies and entered onto pre-designed summary forms. Clinical trials were evaluated for methodological quality using quality criteria developed by the US Preventive Services Task Force. Based on the fulfilment of quality criteria, studies were rated as good, fair or poor. Data Synthesis: Meta-analysis was performed on the data for synthesis, and was carried out for commonly reported outcomes for each medication individually, in comparison with placebo or another drug. Odds ratios (ORs) with 95% confidence intervals for binary outcomes were used. For continuous outcomes, mean differences were used to analyze the data. Meta-analysis revealed that mean weight gain compared with placebo was highest for olanzapine at 3.47 kg (95% CI 2.94, 3.99) followed by risperidone at 1.72kg (95% CI 1.17, 2.26), quetiapine at 1.41kg (95% CI 1.10, 1.81) and aripiprazole at 0.85 kg (95% CI 0.58, 1.13). Olanzapine and clozapine treatment were associated with the highest rate of metabolic laboratory abnormalities in cholesterol and triglycerides. Prolactin elevation occurred with risperidone and olanzapine therapy. Higher odds of extrapyramidal symptoms compared with placebo were seen in children treated with risperidone (OR 3.55; 95% CI 2.04, 5.48) and aripiprazole (OR 3.70; 95% CI 2.37, 5.77). Elevated rates of extrapyramidal symptoms were also experienced with olanzapine use. Conclusions: There is good evidence to support the existence of both metabolic and neurological adverse effects in children treated with these medications. Proper attention and vigilance to potential metabolic and neurological adverse effects is necessary, and should be considered part of the standard of care.

The objective of post-marketing surveillance of medicines is to rapidly detect adverse drug reactions (ADRs). Early ADR detection will enable policy makers and health professionals to recognise adverse events that may not have been identified in pre-marketing clinical trials. Multiple methods exist for ADR signal detection. Traditional quantitative methods employed in spontaneous reports data have include reporting odds ratio (ROR), proportional reporting ratio (PRR) and Bayesian techniques. With the development of administrative health claims databases, additional methods such as sequence symmetry analysis (SSA) may be able to be employed routinely to confirm ADR signals. We tested the time to signal detection of quantitative ADR signalling methods in a health claims database (SSA) and in a spontaneous reporting database (ROR, PRR, Bayesian confidence propagation neural network) for rofecoxib-induced myocardial infarction and rosiglitazone-induced heart failure. This study demonstrated that all four signalling methods detected safety signals within 1–3 years of market entry or subsidisation of the medicines, and for both cases the signals were detected before post-marketing clinical trial results. By contrast, the trial results and subsequent warning or withdrawal were published 5–7 years after first marketing of these medicines. This case study highlights that a post-marketing quantitative method utilising administrative claims data can be a complementary tool to traditional quantitative methods employed in spontaneous reports that may help to verify safety signals detected in spontaneous reporting data.

Recent widespread abuse of cocaine has resulted in an alarming increase in emergency department admissions for acute treatment of this toxic drug. Highly publicised cocaine-associated deaths of prominent athletes have awakened both the medical community and the general public to the possible devastating effects of this so-called ‘champagne of drugs’. A potent central nervous system stimulant, cocaine produces symptoms that include changes in activity, mood, blood pressure, cardiac rhythm, respiration and body temperature. The adverse effects of cocaine, which may progress rapidly to death, include cerebrovascular accidents, myocardial infarction, sudden cardiac arrhythmias, pneumomediastinum, rhabdomyolysis with myoglobinuric renal failure and intestinal ischaemia. In addition, cocaine has been implicated in obstetric and neontal complications. Because of the exceedingly rapid progression of the ‘cocaine reaction’ to a fatal outcome, it is imperative that clinicians know how to recognise and manage the symptoms of cocaine overdose.

Background: Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval. Objective: This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval. Study design: This was a prospective, randomized, double-blind, double-dummy, four-way crossover study. Setting: The study was conducted at a clinical pharmacology research unit. Subjects: Healthy male and female subjects (n = 54) aged ≥50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis. Intervention: Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo. Outcome measures: Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed. Results: All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were −0.91 ms (95% CI −3.33, 1.52) and −1.83 ms (95% CI −4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar. Conclusion: This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.