Current Drug Safety - Volume 5, Issue 2, 2010

Thalidomide is the most notorious example of a drug with serious adverse effects [1] that was initially declared to be safe [2]. This disastrous episode had a major influence on the stringency of pharmaceutical regulation and had a similarly great effect on what could be advertised legally. However, the same stringency does not seem to apply to scientific journals reporting on the safety of drugs. Investigators are allowed to state, in reputable peer-reviewed journals, that a drug is “safe” when they do not have the justification for doing so. Some examples follow. These are from the field of antiepileptic medication but similar examples could be drawn from a number of other therapeutic areas. It must be emphasised that the examples given are from publications in very reputable journals by highly-respected colleagues; the quality of the work is not being criticised but we are advocating a change in terminology and attitude. Felbamate is a broad-spectrum antiepileptic drug that was granted marketing approval in the USA in 1993. The initial publications stated, in good faith, that the drug was safe [3]. The problem is that the statement on safety was based on a trial of only 56 patients treated over a few weeks. Subsequently the potentially life-threatening adverse effects of liver toxicity and aplastic anaemia emerged [4, 5], with the result that the drug is now infrequently prescribed. Vigabatrin was said to be “a safe drug for the treatment of partial seizures” [6]. In 1997, the same year that the first report of serious visual field defects with vigabatrin was published [7], another report stated: “vigabatrin has been shown through several studies to be safe and effective” [8]. Prescribing fell sharply after this adverse effect was reported [9]. Buccal midazolam is now the standard emergency treatment for seizures in paediatric practice in the UK. A very valuable and informative study published in the Lancet, one of the most reputable international medical journals, showed that buccal midazolam was statistically significantly superior to rectal diazepam in the emergency room treatment of status epilepticus in children [10]. This was a landmark paper but why did the authors also conclude, on the basis of only 109 children, that this treatment was safe? It must be emphasised that there is no evidence to contradict this statement but there is also inadequate evidence to support it. If a drug is safe in about 100 patients the mortality rate might still prove to be unacceptably high when information from larger numbers of patients becomes available. It is reassuring to know that no such data of concern have emerged with regard to buccal midazolam but it could be argued that the original statement claiming safety for this treatment was, nevertheless, unjustified. Physicians and patients need to know how safe a drug is but the evidence seems to indicate that we might never be able to declare that a drug is truly “safe”. Infrequent serious adverse effects, including mortality, might not become evident until the drug has been used for several years. We strongly advocate a change in both terminology and attitude. Arguably, to refer to a drug as “safe” is the reassuring terminology of marketing, not of science. Scientific method requires observation and “a safe drug” is not a variable that can be observed. We have many important pre-clinical experiments that look for specific toxicities. In clinical studies we can compare reported adverse events in drug-treated and placebo-treated participants. However, we have no scientific experiment that can prove that a drug is safe. With post-marketing pharmacovigilance, generalisations are made about the tolerability and adverse-event profile of a drug based on a large number of exposures. Conclusions can be proposed about the likelihood of adverse events. However, these conclusions remain probabilities, which may be very unlikely for some drugs, but are never certainties. Journals should refuse to publish papers that claim to have established the safety of a drug on the basis of treatment of a few hundred patients or less. Instead they should insist that authors make more accurate statements. The term “safe” may not be appropriate to describe a drug in scientific writing.“Well tolerated” is more appropriate terminology as it refers to an observation rather than suggesting an inherent characteristic of the drug. For example, instead of “This drug appeared to be safe in the treatment of epilepsy in the 550 patients included in clinical trials” authors should write “This drug was well tolerated in the treatment of epilepsy in the 550 patients included in clinical trials”. If the number of patient years of treatment is large, typically over 100,000, and if this experience is spread over several years, it might be justifiable to state that extensive experience has revealed no serious adverse effects, implying that these are very unlikely to occur. Pharmaceutical companies should also state clearly what the percentage risks of serious adverse effects are, so that the relative safety can be assessed. For example, if an anti-cancer drug increases short-term mortality from 5% to 10% but decreases longterm mortality from 80% to 30%, the patient and physician might still want to give this drug serious consideration. Clinicians prescribing medication have a duty to their patients to provide accurate information so that informed decisions can be made with regard to be risk and benefit. However, they cannot provide this information if they do not have it. The most reliable source of information is generally considered to be reputable peer-reviewed journals. We recommend that journals should not accept unqualified statements about the safety of a drug but should insist that the limitations of the data, particularly with regard to the number of patients treated and the duration of the treatment, should always be specified.

Lung cancer is one of the most commonly diagnosed malignancies and it causes more than 1 million deaths each year worldwide. Small-cell lung cancer (SCLC) accounts for about 15 to 20% of all lung cancers and it is an extremely aggressive cancer, having a response rate of 60-80% with the standard first-line chemotherapy (CT). Topotecan is a topoisomerase I inhibitor currently approved for relapsed SCLC. The authors reviewed the clinical files of SCLC's patients (pts) of a single institution, the Portuguese Institute of Oncology – Porto Centre, in a five year period. The end-points were to evaluate response rates (RR), time to progression (TTP), overall survival (OS) and toxicity profile of topotecan as a second-line treatment of SCLC. >From January of 2002 to December of 2006, 146 pts were diagnosed with SCLC, 32 were submitted to second-line treatment and 23 with topotecan. The RR was 17.4%, median TTP and median survival after topotecan were 2.8 months and 6.3 months, respectively, and median OS was 17.5 months. The incidence of grade 3 and 4 adverse events was 16.6 and 2.6%, respectively. Topotecan showed clinical activity in our unselected daily patients with relapsed SCLC, with acceptable toxicity, in accordance with the published literature.

Black cohosh (Actaea racemosa L. [syn. Cimifuga racemosa L.]) extracts (BCE) are marketed worldwide for the management of menopausal symptoms. However, recently more than 75 cases of hepatotoxicity associated with black cohosh ingestion have been reported. While these cases have not been fully substantiated for causality, the data suggest that herb-drug interactions may be involved rather than a direct hepatotoxic event. This work describes the in vitro inhibition of four CYP450 enzymes (1A2, 2D6, 2C9, 3A4) by black cohosh extracts and identifies the active inhibitory constituents. Ethanol extracts (75 and 80% ethanol) and a 40% isopropanol extract induced a concentration-dependent inhibition of all CYP450 isozyme activities, with median inhibitory concentrations (IC50) ranging from 21.9 μg/ml to 65.0 μg/ml. Isolation of the active chemical constituents, showed that the triterpene glycosides were weakly active (IC50 25-100 μM), while fukinolic acid and cimicifugic acids A and B strongly inhibited all CYP isozymes (IC50 1.8-12.6 μM). None of the extracts inhibited the growth of Hep-G2 cells in concentrations up to 50 μg/ml. These data suggest that BCEs are not directly hepatotoxic, but may have the potential to induce herb-drug interactions, which may in turn explain the rare cases of hepatotoxicity observed in women using multiple medications and dietary supplements, including black cohosh.

Nitrofurantoin lung toxicity was diagnosed among ten patients receiving 50 mg/day to prevent recurrent urinary tract infection. In six patients a symptomatic period of 3-36 months preceded the diagnosis. All but one patient, with irreversible lung injury at presentation recovered completely, five after drug discontinuation and four after steroids therapy. Large amount of data regarding unexpected, sometimes severe pulmonary toxicity during nitrofurantoin therapy should maintain a high index of suspicion for the drug usage among patients with non-resolving pulmonary symptoms. Alternatively, the use of other antimicrobial agents with a better risk-to-benefit ratio should be considered.

Restless leg syndrome (RLS) is a common disorder associated with significant distress. We report three cases of drug induced RLS caused by olanzapine. In each case, RLS commenced after initiation of treatment with olanzapine and resolved after ceasing olanzapine. All three patients were subsequently treated with other atypical antipsychotics, risperidone, quetiapine or aripiprazole, without re-emergence of RLS. RLS is associated with central dopaminergic dysfunction. Dopamine agonists and l-dopa reduce the symptoms of RLS, and some agents that block the dopaminergic system aggravate RLS. Greater awareness of potential causes of RLS, and its differentiation from akathisia and illness related agitation might help in reducing the distress associated with it and improving patient compliance.

Formal retraction notice of article entitled Clinical Management of Postoperative Vomiting after Strabismus Surgery in Children (Curr Drug Saf. 2010 Apr; 5(2):132-48) by Dr Y. Fujii. This article is being retracted as a result of: Failure of Dr. Fijii's institution as well as of himself to rationalize the legitimacy of the study and/or its data as stipulated in request by the Editors-in-Chief of the journals extended on April 9, 2012. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Paliperidone, the active metabolite of risperidone is a relatively recent introduction for the treatment of schizophrenia. There is paucity of data regarding the use of paliperidone in elderly patients. We have attempted to highlight the prominent aspects of the use of paliperidone in the geriatric population. The limited data indicate that paliperidone may be effective and safe in the treatment of schizophrenia in the elderly.

Over the past 15 years, the number of studies investigating the potential teratogenic effects of antidepressants has drastically increased. Prescribing antidepressants during pregnancy is becoming a challenge for health care providers because of conflicting data on their teratogenic potential. A critical systematic review of studies describing the relationship between antidepressant use during pregnancy and its impact on congenital malformations, prematurity, low birth weight (LBW), and child development was undertaken to summarize the current evidence-based findings. Most antidepressants do not pose a major teratogenic risk, although the data supporting this conclusion vary from one type to another. While SSRIs and tricyclics have been examined in a considerable number of studies, only scarce data is available on new antidepressants. The use of paroxetine during organogenesis has been linked to an increase in the risk of cardiovascular malformations. The impact of prenatal exposure to antidepressants on prematurity and LBW remains controversial, and most studies evaluating these outcomes are limited by their small sample size and lack of adequate reference group. Finally, information on the long-term effects of gestational antidepressant use on child development is only starting to emerge, and existing information is too limited to determine the risk.

The thrombopoiesis-stimulating agents (TSAs) are a novel class of drugs for the treatment of chronic immune thrombocytopenia (ITP). Roimplostim and eltrombopag, the first two TSAs to enter clinical use, received regulatory approval in 2008 and stand poised to change the treatment paradigm in ITP. However, important questions regarding the safety of these agents, particularly with long-term use, remain partially unanswered. The primary objective of this article is to review the reported toxicities associated with the TSAs including rebound thrombocytopenia, thrombosis, hepatotoxicity, formation of neutralizing antibodies, bone marrow fibrosis, hematologic malignancy, cataract formation, and common adverse events. The incidence and severity of these toxicities as well as strategies for monitoring patient safety and pharmacovigilance are discussed.

Glucocorticoid therapy, the mainstay treatment of many chronic diseases, has many complications including osteoporosis. Premenopausal women requiring glucocorticoids are at a significant risk of developing glucocortiocoid-induced osteoporosis. Bisphosphonate therapy is a vital option in the prevention and treatment of glucocorticoid-induced osteoporosis. Animal studies with bisphosphonates have displayed maternal toxicity, foetal underdevelopment, embryolethality, hypocalcaemia and skeletal retardation during pregnancy. Bisphosphonates are therefore contra-indicated in pregnancy and have a FDA category C pregnancy risk. Their use in premenopausal women prior to conception may also pose a teratogenic risk because bisphosphonates remain in mineralised bone for several years. Consequently a clinical dilemma exists in treating and preventing glucocorticoid-induced osteoporosis in premenopausal women. This article aims to review the available evidence regarding the use of bisphosphonates in premenopausal woman. Bisphosphonate treatment of metastatic hypercalcaemia during pregnancy has not demonstrated adverse foetal events. Cases of preconception bisphosphonate exposure have failed to describe developmental or bone density abnormalities, however neonatal hypocalcaemia has occurred. Lower birth weight, lower gestational age at birth and higher rate of spontaneous abortion in mothers with preconception and first trimester bisphosphonate exposure have been described, however notable confounding factors and lack of adequate sample size make extrapolation of this data difficult. Human preconception and first trimester bisphosphonate use has to date not been associated with the same adverse effects evident in animals. Larger well-controlled studies in premenopausal women with preconception and peri-natal bisphosphonate exposure are required to confirm the safe use throughout pregnancy to both mother and foetus.