Current Drug Safety - Volume 3, Issue 2, 2008

We consider the management of safety signals that arise in the context of endpoint trials. Such trials have design features which permit the detection of signals that otherwise may be missed in more traditional settings. However, the approaches that are typically employed to address them are less than satisfactory in terms of both the analytical techniques and the communication of the findings. In this paper, alternative approaches are evaluated, and recommendations are given for a comprehensive strategy that involves appropriate use of study data as well as information external to the study. It is emphasized that formulation and implementation of an effective communication plan that enables informed decision making should be an integral component of the strategy.

Infections are relevant complications that cause morbidity in solid organ transplantation and autoimmune diseases. Infection represents a leading single cause of death in these patients. Identification of patients at risk for development of infections and specific intervention to decrease infection risk might lead to better outcomes, though one needs first to evaluate the presence of risk factors for infection. Underlying disease itself, activity of the disease, presence of co-morbidities, transplantation procedures along with immunosuppressive and immunomodulatory therapies may be associated with an increased risk of infections. Among host factors, there are no reliable immunological markers to predict infections. Immune monitoring (assessment of immunocompetence) to estimate the risk of infection has so far not been performed routinely, with the only exception of neutrophil counts, tuberculin skin testing and serological evaluation of donor and recipients of transplants for anticytomegalovirus IgG antibodies. However, alterations of specific and non specific humoral and cellular immunity may be associated with a higher risk of infection among immunosuppressed patients. We review studies that have been designed to assess immune monitoring for prediction of infections in patients with selected solid organ transplantations and systemic autoimmune diseases.

As part of the intensive efforts in facilitating drug discovery, computational methods have been explored as low-cost and efficient tools for predicting various toxicological properties and adverse drug reactions (ADR) of pharmaceutical agents. More recently, machine learning methods have been applied for developing tools capable of predicting diverse spectrum of compounds of different toxicological properties and ADR profiles. Based on the results of a number of studies, these methods have shown promising potential in predicting a variety of toxicological properties and ADR profiles. This article reviews the strategies, current progresses, underlying difficulties and future prospects in using machine learning methods for predicting compounds of specific toxicological property or ADR profile.

The recognition, management, and if possible prevention, of major cardiovascular, central nervous system, haematological, and metabolic adverse effects, including diabetes mellitus and weight gain, of antipsychotics and some other drugs used to treat mental illness is a topic of much debate. However, a wide range of other adverse effects, some of which may be life-threatening, may also be encountered. Side-effects reviewed here include: gastrointestinal-associated effects (constipation, hypersalivation, oropharyngeal lesions, nasal congestion, nausea, nocturnal enuresis, and urinary retention), metabolic effects (obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, and hypertension), neuromuscular effects (extrapyramidal side effects, myoclonus, and neuroleptic malignant syndrome, and pleurothotonus), thermoregulatory effects, effects on the liver, pancreas, and kidney, sexual side effects, and effects on skin and bone. Metabolic factors affecting the incidence of adverse effects to clozapine especially are also discussed. The increasing use of atypical (second generation) antipsychotics and indeed of selective serotonin reuptake inhibitors has led to a greater appreciation of not only the benefits of these drugs, but also of the spectrum of toxicity that may occur in clinical practice. The adverse effects of antipsychotics are a major factor in promoting poor adherence to, and even discontinuation of, antipsychotic treatment on the one hand, and increasing the risk of cardiovascular and metabolic disease on the other. As such they merit recognition and either harm minimization strategies (use of the minimum effective dose, or use of lower doses of combinations of antipsychotics), or in extreme cases discontinuation of the offending drug(s).

Purpose: To estimate the rate of new-onset seizure in ADHD patients in relation to ADHD pharmacotherapy. Methods: A retrospective cohort study of 34,727 patients, ages 6 to 17, with at least two insurance claims bearing ADHD diagnoses during 2003 in the United Healthcare database. Incidence of seizure was calculated for observation time during treatment with atomoxetine and stimulants/bupropion. Results: Seizure incidence among ADHD patients was 4.5/1,000 person-years (p-y; 95% confidence interval 3.7 - 5.5). ADHD patients who received any ADHD medication had an incidence of 3.8/1,000 p-y (3.0 - 4.8) compared to 8.7 (5.8 - 12.4) for patients who did not receive any ADHD medication. The relative risk (RR) for current vs non-use of atomoxetine was 1.1 (0.6 - 2.1). For stimulants and bupropion, the RR for current vs non-use was 0.8 (0.6 - 1.3). Elevated seizure risks were found in association with central nervous system (CNS) disease (OR 3.9, 1.2 - 10.9), CNS medications (OR 2.2, 1.3 - 3.6), metabolic disease (OR 2.9, 1.1 - 6.8), and psychiatric disease risk factors (OR 1.7, 1.1 - 2.6). Conclusions: In this study, there was no statistically significant association between use of atomoxetine or stimulants and seizure risk in children ages 6 to 17 years with ADHD and without prior seizure disorder.

Objective: Review nonclinical and clinical trial data for hepatic effects of duloxetine. Methods: Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials. Results: Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases >3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hy's rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each). Conclusions: Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.

Objective: Review spontaneous reports and epidemiology of hepatic events associated with duloxetine. Methods: Spontaneous reports of adverse events potentially associated with hepatic injury were identified. Classification schemes were Clinical Significance and Etiologic Category relative to likelihood of being related to duloxetine. Results: Duloxetine has been taken by an estimated 5,083,000 patients, representing approximately 1,551,000 personyears (PY) of worldwide exposure. In the Etiologic categorization of the 406 cases containing event terms potentially related to the liver that have been reported to the manufacturer, 26 were deemed Probable and 127 Possible. Because of scantly-reported information, 182 cases were considered Indeterminate. For Severe Hepatic Injury, the observed spontaneous reporting rate was 0.7/100,000 persons exposed. Of the 406 cases, 225 experienced enzyme elevations to values <500 U/L, most with concentrations well below this level. The calculated cumulative spontaneous reporting rate of all duloxetine hepatic-related events combined was 0.00799%, in the context of other drug-induced hepatic injury rates reported in the literature of 0.7 to 40.6 per 100,000 PY of observation. Conclusions: There were few cases of true hepatic injury possibly or probably related to duloxetine. The calculated cumulative reporting rate is consistent with very rarely reported per the Council for International Organizations of Medical Sciences.

Objective: Present results from two hepatic safety studies conducted within 20 months after duloxetine launch. Methods: Signal detection based on spontaneous reports to the FDA adverse event reporting system (AERS) and on a comparison of duloxetine and venlafaxine in the i3 Drug Safety Aperio claims database, using measures of disproportionality and incidence rate ratio, respectively. Results: In AERS all antidepressants had some degree of association with hepatic injury, in that at least one hepatic event was disproportionately represented for each drug. Signals were detected for duloxetine cases analyzed against full and antidepressant- only backgrounds. These signals corresponded to labeled events or events investigated during ongoing surveillance. Using a duloxetine fatal-case series, disproportional representation of clinically serious events was detected relative to both backgrounds, but the signals were refuted upon independent expert panel case review. The Aperio study showed no difference in hepatic injury between duloxetine and venlafaxine initiators after proper control for baseline risks, suggesting differential prescribing of duloxetine, perhaps preferentially as second-line therapy in some initiators. Conclusions: No new signals were identified in Aperio. New signals detected through AERS were refuted upon independently conducted case-level investigation. Hepatic signals arising from spontaneously reported data must be clarified through subsequent systematic investigation.

The objective of the study is to assess the frequency and comprehensiveness of laboratory monitoring of hematological and hepatic parameters in ambulatory Nigerian hypertensive patients on methyldopa therapy. A retrospective cross sectional study was conducted between 1st February and 31st March 2007 at the Medical Outpatient Clinic of a 900-bed premier teaching hospital located in Ibadan, Nigeria. 260 case notes of hypertensive patients, out of the 1178 case notes of patients who had been prescribed at least 250mg of methyldopa for at least 2 months, were reviewed. 22.1% of the hypertensive patients were on methyldopa alone or in combination with other anti-hypertensives for a mean period of 26.8±2.3 months (Range: 2-36 months). Overall, red cell count was prescribed and conducted in only 15.4% (40) of cohort. Only 4.2% (11) of patients had follow-up red cell count done after one month of methyldopa therapy; 9 out of these patients had marked reduction of red blood cells. Only 2.3% of cohort had baseline Liver Function Test (LFT) before start of methyldopa therapy and Alanine Transaminases and Aspartate transaminases levels were elevated in all patients. No patient had subsequent LFT prescribed and conducted particularly within 6-12 weeks of use of methyldopa. Direct Anti-Globulin Test was neither prescribed nor conducted in any of the cohort before and after commencement of methyldopa therapy. In conclusion, laboratory monitoring of ambulatory hypertensive patients on methyldopa therapy particularly for possible hematological and hepatic toxicities is less than optimal. The consequent therapeutic benefit of continuing considerable prescription and use of methyldopa in Nigeria is less likely to be realized without proper monitoring to preclude possible methyldopa- use related harms.