Current Drug Safety - Volume 6, Issue 1, 2011

It could be argued that the primary aim of drug safety investigations is to determine factors related to the frequency and severity of adverse effects so as to minimise them. Second only to efficacy, adverse effects of the drug are of major importance. Both patients and clinicians are keen to know about adverse effects before deciding whether the benefits of taking any drug outweigh the potential risks. However, adverse effects are not always easy to determine. In this context it is very important to distinguish between adverse effects, adverse events and side-effects. Some working in the field of drug safety might consider it quite unnecessary to discuss the difference between these terms but regrettably, many papers offered to scientific journals do not use the terminology in a scientifically correct way. How are these terms defined? Wikipedia [1] provides the following definitions. “‘Side effect’ can mean: a ‘therapeutic effect’, an unintended but desirable consequence of medical treatment or an ‘adverse effect’, an unintended and undesirable consequence of medical treatment or an adverse drug reaction, such an effect caused by a drug.” In relation to adverse effects of drugs, the term “adverse drug reaction” is equivalent to “adverse effect”. The broader term “adverse event” is sometimes restricted to clinical trials but there is no reason why this should be the case. How are adverse effects to be distinguished from adverse events? Consider the following hypothetical situation. After a baseline evaluation period of one month, a new drug is prescribed to a group of patients for a further month. In this trial patients act as their own controls. The drug is, accordingly, withdrawn for one month to determine whether any adverse events during the treatment period were genuinely associated with the drug or simply occurred by chance. The entire group has an adverse event that potentially affects quality of life in a major way and which was not present in the baseline period nor in the subsequent period after the drug had been stopped. Some might argue that there is no doubt whatever that this major adverse event was an adverse effect, since the patients were acting as their own controls and the adverse event was not experienced before or after the drug was taken. However, if the major adverse event was that none of them was able to fly in an aeroplane during the drug treatment, they all resided in the UK and the period during which they were treated happened to coincide with the volcanic eruption in Iceland that grounded all aircraft, it is immediately clear that the major adverse event was certainly not an adverse effect of the drug. This simple hypothetical example is intended to illustrate that adverse events are not necessarily adverse effects, even if there appears to be quite strong evidence suggesting that they might be. Drug trials can provide good data on adverse events but seldom provide good data on adverse effects. The determination of whether an adverse event is an adverse effect depends on a number of factors. If an adverse event occurs with a statistically significantly higher frequency in the treatment group than in the placebo group in well-designed, randomised, double-blind, placebo-controlled trial on well-matched groups of patients there is a stronger basis for judging it to be an adverse effect rather than a chance association or the result of some confounding issue. However, other factors will also influence the assessment of whether an adverse event is an adverse effect. The time relation to the prescription of the drug may be important, although it should be noted that some adverse effects may not appear until the drug has been taken for several weeks or, indeed, for years [2]. If an adverse event otherwise occurs rarely but is consistently associated with a particular drug, then it becomes much more plausible to consider that it might be an adverse effect of the drug. This introduces the concept of “plausibility” but it would be unwise to over-emphasise the role of plausibility without a strong basis for doing so. For example, if a drug is found to be associated with a higher rate of road traffic accidents in drivers this might not immediately appear to be a plausible association but the possibility that the medication concerned might be affecting judgement or impulsivity would have to be considered. On the other hand, if a particular drug were associated with an increased risk of being killed by lightning, the plausibility of a causal association would be very low and, in that case, the adverse event would be unlikely to be an adverse effect. Pharmacovigilance provides a very important means of collecting drug safety data, particularly with regard to rarer adverse events. However, it is again important to distinguish between adverse events, which may be associated with taking a drug, from adverse effects that are the result of taking that drug. Patients treated for depression with selective serotonin reuptake inhibitors (SSRIs) are at increased risk of having seizures. If a group of people in the general population, matched for age, sex, educational status and other factors is compared with a group of people taking SSRIs, the second group would have more seizures. This clearly demonstrates that SSRIs are associated with seizures. However, it does not demonstrate that SSRIs cause seizures. One of the commonest indications for SSRIs is depression, which is a major risk factor for seizures. The wrong choice of comparison groups has been made; if a group of depressed people treated with placebo is compared with a group of depressed people treated with SSRIs, the latter group has less not more seizures, suggesting that, far from precipitating seizures, SSRIs may protect against them [3]. Again, very careful evaluation needs to be made before drawing any conclusions with regard to causality. The term “side effect” can refer to any effect, either beneficial or harmful, of the drug other than on the condition or symptom that is the target indication for that drug. One of the prime examples of a drug that had a notable side effect which was not considered to be an adverse effect is sildenafil citrate (Viagra) [4]. This was initially prescribed to treat angina but was found to have a side effect that some of the patients considered to be beneficial. It has subsequently attracted a major market for what was originally considered to a side effect. Other side-effects are used intentionally by prescribers in certain situations. For example, weight loss, which can occur with the antiepileptic drug topiramate [5], may be considered to be either an adverse effect or a beneficial effect, depending on the patient. The patient who is overweight might choose this drug in preference to sodium valproate [6], which can be associated with weight gain. Some antiepileptic drugs can also have beneficial or adverse effects on mental state. For example, carbamazepine and valproate are viewed as mood-levelling drugs [7] and, in addition to their use in psychiatric patients who do not have epilepsy, they might be chosen to improve seizure control in a patient with epilepsy who also had a mood disorder, in preference to the drug such as topiramate, which is associated with depression. Should these beneficial effects still be considered as “side effects” or should they be viewed as a secondary indication for prescribing the chosen medication? .......

Introduction: The main objectives of this study were to estimate the prevalence of and the risk factors for the adverse effects of tacrolimus-based immunosuppression in patients who obtained renal transplant from living donors. Methods: A multicenter cross-sectional observational study in 154 kidney transplant patients who received grafts from living donors. Results: Large proportion of patients had hypertension (83%) and hyperlipidemia (53%); 27% had posttransplant diabetes mellitus. Patients had on average two chronic diseases. Tremor was present in 40%, neurologic toxicity in 45%, and anemia in 51.5% of patients. The average number of adverse effects was 3.52 ± 1.57. In multivariate analysis some adverse effects were related to tacrolimus concentration, duration of treatment, number of medications or medical problems. In linear regression analysis correlation was found, among the others, between diastolic blood pressure and tacrolimus concentration, and inverse correlation between erythrocyte count and duration of treatment. Conclusion: There is a significant prevalence of tacrolimus adverse effects and supratherapeutic TAC blood concentrations in Jordanian renal transplant patients in spite of using low TAC doses and overall adequate renal function.

Objective: To assess the effect of recent availability (due to more home use) of methadone and buprenophine has had on the accidental and non-accidental misuse by children. Methods: A retrospective review of all pediatric (< 18 years old) admissions for methadone or buprenorphine ingestion at Eastern Maine Medical Center (EMMC) from September 1, 1999 to August 31, 2009 was performed. Data recorded included age, sex, accidental or non-accidental ingestion, source of drug, ward or pediatric intensive care unit (PICU) admission, treatment given and length of hospital stay. Relation to pediatric emergency department (ED) visits, general pediatric ward admissions and patients on opioid maintenance treatment in the area was also assessed. Results: There were 22 children (12 female) admitted for methadone (10, 46%) or buprenorphine (12, 54%) ingestion, with ingestions tripling in the later five year period compared with the earlier five years. The trend was statistically significant, unrelated to pediatric ED visits or ward admissions but statistically related to number of patients on opioid maintenance treatment in the region. Of the 22 children with ingestion, six (27%) were adolescents (mean age 15.2 years) and ingestion was intentional (three suicide, three recreational) and 16 were infants or toddlers (mean age 21.6 months) whose ingestions were accidental. The drug source was family and friend (18, 82%) or unknown (four, 18%). There were six patients admitted to the ward and 16 patients (74%) admitted to the PICU. Two patients had observation only, seven had anticipatory intravenous (IV) line placement, nine patients were given IV line and naloxone (bolus ± IV infusion), and four patients required endotracheal intubation, IV placement and naloxone. There were no fatalities and mean hospital stay was one to seven days, mean 2.3 days. All families were referred to family services. Conclusions: Accidental and non-accidental ingestion of methadone and buprenorphine by children is increasing in proportion to increased clinical use and availability. Health providers should be aware of this increased risk and be able to provide appropriate treatment and family support.

Purpose: The goals of this study were to identify the frequency of N-acetyltransferase-2 genotypes and phenotypes in Iranian tuberculosis and healthy subjects and to evaluate correlation of acetylator phenotype and antituberculosis-induced hepatotoxicity in pulmonary tuberculosis patients. Method: A total of 50 newly diagnosed pulmonary tuberculosis patients and 50 healthy Iranian subjects were enrolled in the study. A combination of polymerase chain reaction and restriction fragment length polymorphism were used to investigate N-acetyltransferase-2 alleles. The tuberculosis patients were followed for occurrence of antituberculosis induced hepatotoxicity during the treatment course. Correlation between N-acetyltransferase-2 phenotypes and antituberculosis induced hepatotoxicity was evaluated. Results: Frequency of slow, intermediate and fast acetylator genotypes in the healthy group were 32%, 54% and 14 % and in the tuberculosis patients were 28%, 64% and 8%, respectively. Hepatotoxicity was detected in 64.3% of slow acetylators, 15.6% of intermediate acetylators and interestingly in none of the fast acetylators. Conclusion: There were no significant difference in distribution of various N-acetyltransferase-2 alleles, genotypes and phenotypes between pulmonary TB patients and healthy individuals. Among patients, anti-tuberculosis induced hepatotoxicity was more frequent in slow acetylators in comparison with fast acetylators in Iranian tuberculosis patients.

Purpose: To determine whether lamotrigine affects serum concentrations of valproic acid. Methods: Pre-morning-dose serum valproic acid concentrations were measured in 76 subjects with epilepsy (48 M, 28 F, age range 6-20 years, mean age 14 years) in whom lamotrigine was added while the dose of valproate and other medication remained unchanged. In a comparison group, either acetazolamide or gabapentin was added to sodium valproate. Results: Far more subjects (26/76=34%) had an increase of >25% in valproic acid concentration with lamotrigine than those who had a decrease of >25% (4/76=5.3%). The mean valproic acid concentration before starting lamotrigine was 61.0 mg/L and on lamotrigine was 67.1 mg/L; the difference in means was 6.1 mg/L (standard error 2.1, 95% confidence limits 2.0, 10.2, p=0.004, highly significant, paired sample t-test, two-tailed), a rise of 10%. The change in valproic acid concentration appeared to depend on the initial valproic acid concentration (Pearson r=-0.405, p<0.001). In 14.5% of the subjects the increase in valproate concentration was >50%, which could lead to toxicity, although the increase tended to occur with lower or intermediate initial valproic acid concentrations whereas a small overall decrease in valproic acid concentrations with lamotrigine was found with the higher initial valproic acid concentrations. One subject had abnormal bruising with the increased valproate level after lamotrigine was added, which resolved on decreasing the valproate dose. The changes in valproic acid concentrations in the comparison group were small (mean increase 2.6%) and were not statistically significant. Conclusions: Although there is a wide variation in the changes of valproic acid concentrations when lamotrigine is added, the concentrations tend to increase rather than decrease, especially with low or intermediate initial valproic acid concentrations. In some cases valproate toxicity, manifested by abnormal bruising, may result, although at higher initial valproic acid concentrations the valproic acid concentration usually tends to fall slightly with the addition of lamotrigine.

Pharmaceutical manufacturer labels are an important source of adverse drug event (ADE) information. The study objective was to determine the sufficiency of ADE reporting in US drug labels. A sample of 50 labels was evaluated from the top 200 drugs dispensed in the US. Electronic copies of labels were obtained and reviewed by 2 pharmacists for ADE incidence and discontinuation data. ADE incidence data were provided in 86% of labels. However, discontinuation rates due to ADEs and ADE incidence by dose were only reported in 60%. ADE incidence reporting by age (46%) or gender (18%) was also low. ADEs that occurred in less than 2% of the population were rarely reported. Incidence rates were based on small populations (median of 794) and short term studies (median of 84 days for chronic conditions). Labels for 19 drugs used chronically had no long term study data. Methods for collecting ADE data were stated in only 12% of labels. Adverse drug event and drug discontinuation data is under-reported in US labels. More information on adverse events causing discontinuation (especially serious events) and those related to dose, age, and gender is needed in labels to ensure safe prescribing and dispensing of drugs.

The pro-drug codeine is commonly prescribed for postpartum pain relief in North America. The safety of codeine during breastfeeding is related in part to the extent of the active morphine metabolite catalyzed from codeine via the cytochrome P450 2D6 (CYP2D6) enzyme. In mothers who have greater than two functional copies of the CYP2D6 gene (CYP2D6 ultrarapid metabolism phenotype; UM) a substantially higher proportion of morphine is produced. Label changes on codeine-containing medications will highlight the risks associated with this genotype for breastfeeding mothers, but are not supported by translation strategies on how to incorporate this pharmacogenetic knowledge into clinical practice. To address the immediate issue of CYP2D6 UM inheritance in family members of a breastfed infant who succumbed to fatal opioid intoxication and whose codeine-prescribed mother was a CYP2D6 UM, we constructed a pedigree. While the pedigree approach is helpful to aid diagnosis, identify other at risk family members, and simplify pharmacogenetic analysis, its clinical usefulness is dependant on an institutional framework which is not available in most centers at this time.

We describe a unique new collaboration which allows linkage of administrative databases in Southern Israel, and hence ascertain risk/safety of prescription drugs in pregnancy. The advantages of this system include availibilty of rigorous data confounders, solid data on maternal conditions for which the drug is given, ability to capture all cases of elective abortions and not just live births, and ability to construct drug doses.

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical. Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI. Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed. No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI. Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate that case having been reported in a patient randomized to treatment with placebo. Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.

Under normal circumstances, children are excluded from clinical trials of new drug candidates. Yet, when the drug product is approved for marketing by the authorities, it is only a matter of time before physicians use that drug on pediatric patients. We do know that the practice of prescribing drugs for off-label conditions is found in approximately 50% of all physician prescribing. We should not look at off-label pediatric drug use as always a bad or negative behavior. It may be that a manufacturer has conducted a successful clinical trial for a new pediatric condition and has submitted the documentation to the FDA staff to support that new indication, but the regulatory agency has not completed its review and formally awarded the new indication to the sponsor. Or it might be the case that over a dozen years of clinician experience informs all clinicians that an offlabel use of a drug works most effectively and yet the manufacturer is reluctant to spend the money required for a supplemental investigation when it loses patent protection in under a year. As with many other situations where not all of the facts may be known, it seems that the wisest path is to approach the use of drugs for off-label conditions with great caution and with as much knowledge as may be gained before the prescribing decision is arrived at.

Oculogyric crisis (OGC) is an acute dystonia which can occur after initiation of antipsychotic treatment. Stereotypic paroxysmal psychiatric symptoms have been described along with OGC that resolve spontaneously when the later remits. We report a case of tardive OGC associated with zuclopenthixol in which there were associated paroxysmal auditory pseudohallucinations.

We report three cases of pathological gambling induced by Aripiprazole, in patients with schizophrenia or schizoaffective disorder. All three patients had no history of pathological gambling, and they started gambling after initiation of treatment with Aripiprazole. The fact that pathological behavior disappeared quickly as medication ends suggests that an elaborate behavioral manifestation could be related to dopaminergic tone in patients with schizophrenia. We recommend consideration with increased attention for the appearance of pathological gambling symptoms among patients on Aripiprazole.

A potential interaction between valproate (VPA) and doripenem leading to decreased valproic acid concentrations in two patients is described. In the first patient case, a 54-year-old female presented to the emergency department following a seizure episode after stopping her medications a few days prior. She was given a 1500 mg (23 mg/kg) intravenous (IV) bolus dose of valproate and restarted on her home regimen of divalproex sodium 750 mg daily which quickly resulted in valproic acid blood concentrations within the reference range. The patient was later started on doripenem 500 mg IV every 8 hours and subsequent valproic acid concentrations decreased by 62%. The second patient was a 54-year-old female transferred from an outlying facility following a motor vehicle accident. The patient was receiving valproate 1250 mg IV every 8 hours for seizure prophylaxis following a traumatic brain injury. She developed pneumonia and was started on doripenem 500mg IV every 8 hours. Valproic acid concentrations decreased by 69% within two days. This case report describes two patients receiving concomitant valproate and doripenem resulting in a 62% and 69% reduction in valproic acid concentration.

Varenicline is a drug specifically developed for smoking cessation. Gastrointestinal symptoms are among the most common side effects (nausea, vomiting, and constipation). Here, we described the case of a 75 year-old man who suffered from functional adynamic ileus while taking varenicline. Adynamic ileus is a rare condition during treatment with varenicline. Clinicals should be aware of this side effect becuase it could lead to varenicline withdrawal and reconsideration of patient smoking cessation strategy.