Current Drug Safety - Volume 6, Issue 3, 2011

Skepticism is an essential quality in science. We doubt, re-examine and demand the highest quality of evidence. However, sometimes this puts us in an awkward situation. How much evidence do we need before we act? This dilemma is a constant problem in drug safety. Treatment decisions are always a balance of risks and benefits and there may be a paucity of evidence about rare or very rare adverse events. Recently, two important nested case-control studies have been published that have brought drug safety once again into the spotlight of the global media. A study using the UK general practice research database [1] and a study using a US database of claims paid by managed care plans [2], with both studies concluding that oral contraceptives containing drospirenone had an increased risk of venous thromboembolism (VTE) compared to earlier generation oral contraceptives. Earlier studies from Denmark and the Netherlands that reached similar conclusions had been criticised for methodological concerns [3]. Other studies have not found an increase in VTE with drospirenone containing oral contraceptives compared to other oral contraceptives [4]. It has been argued that estrogen independent of progestogen is the cause of VTE associated with oral contraceptives [3]. Previous generations of oral contraceptives are also associated with an increased risk of VTE and reports of this increase risk resulted in changes in prescription patterns, which may have led to fewer cases of VTE [5]. To add to this dilemma, risk of VTE is compounded by other risk factors, including age, obesity and smoking [6]. Given the evidence, our strategy as always is to balance the risks and benefits of treatment. Regulatory bodies at a population level, clinicians and their patients at an individual level. The risk of VTE associated with drospirenone containing oral contraceptive use is very low, however it is a serious and sometimes fatal adverse effect. The benefits of oral contraceptives on an individual's lifestyle may be enormous, as has been the impact of oral contraception on societal change. However, these are not health benefits and attempting to balance them against a health risk requires assigning a subjective value to them. Additionally, many other forms of contraception are available, including earlier and possibly safer forms of oral contraception. Then there are inter-individual differences, where for some people substituting one form of contraception for another is simple, whereas for others it is unimaginable. Given the level of complexity, most people will quite rightly turn to the regulatory authorities and leading scientists and academics for guidance. The U.S. Food and Drug Administration (FDA) issued a communication giving useful advice, but not taking a firm stand one way or the other with regards to the safety of these drugs. They are waiting for the results of their own review [7]. Recent guidelines from the Society of Obstetricians and Gynaecologists of Canada (SOGC) firmly conclude that there is no increased risk of VTE with drospirenone containing oral contraceptive and suggest that concerns over safety are a media driven “pill scare” [8], however, these guidelines were written prior to the publication of the two recent studies that have caused the latest controversy.....

Purpose: The aim of this study is to evaluate patients' demographics, patterns of presentation and outcomes of admissions with severe hyponatremia and other electrolyte disturbances that are related to indapamide. Methods: Patients with severe indapamide-related hyponatremia (defined as serum sodium <125 mmol/L) admitted to the Department of General Medicine of a tertiary teaching hospital between 1 July 2006 and 30 June 2009 were evaluated in this study. Patients' characteristics, clinical features of their presentation and other electrolyte disturbances were analyzed retrospectively. Results: Eleven patients were admitted with severe hyponatremia and other electrolyte disturbances associated with indapamide use. All patients were female and elderly (age: 81.7 ± 5.8 years). Their mean weight was 59.0 ± 8.8 kg. Indapamide sustained release (SR) 1.5 mg daily was taken by eight of eleven patients and the others took indapamide 2.5 mg in combination with perindopril. The mean serum sodium concentration on presentation was 110.9 ± 5.9 mmol/L and was associated with findings of hypokalemia in ten patients and hypomagnesemia in eight patients. All patients presented predominantly with neurological manifestations, delirium (six patients) being the most common. Electrocardiographic changes were common (nine patients) including prolonged QT interval in six patients. All the patients' electrolyte abnormalities were corrected without any life-threatening complications. Conclusions: This study highlights that the use of indapamide is associated with severe hyponatremia and other electrolyte disturbances. Therefore clinicians should be aware of severe electrolyte disturbances arising from indapamide. New onset of neurological symptoms such as delirium and unsteady gait in the elderly taking indapamide should prompt evaluation of their electrolyte profile.

We assessed the safety and efficacy of different nevirapine-based regimens in patients starting this drug in a large cohort of Caucasian subjects during the 1999-2007 periods. Methods. A retrospective database review of all patients receiving nevirapine was performed; clinical, biochemical (hepatic and metabolic profiles), immuno-virological parameters were evaluated in the overall population and in different subgroups (according to gender, therapy-experience and HBV/HCV co-infection). We determined risk factors related to dyslipidemia development and to nevirapine interruption within 1 year. Results. We evaluated 277 patients; 58 (20.9%) were naïve, 180 (65&percnt) females and 137 (49.5%) HBV/HCV co-infected. After 48 weeks, 73.6% patients continued antiretroviral regimens. Among these, nevirapine showed little hepatic and metabolic impact, as well as good immuno-virological outcome despite sex, drug experience and co-infection. Factors related to development of dyslipidemia were higher in total cholesterol, female gender with high CD4 count and male gender with low CD4 count (p<0.05). Factors related to discontinue nevirapine were age and HBV/HCV co-infection (p<0.05). Conclusions. We observed a high rate of discontinuation probably because of the special composition of our population (huge proportion of women and co-infected individuals). Nevertheless, nevirapine was a well-tolerated drug with a favorable impact on hepatic, metabolic and immuno-virological parameters in all the analyzed subgroups.

Purpose: To assess the reporting rates of serious adverse events attributable to yellow fever vaccination with 17D and 17DD strains as reported in pharmacovigilance databases, and assess reasons for differences in reporting rates. Methods: We searched 9 electronic databases for peer reviewed and grey literature (government reports, conferences), in all languages. Reference lists of key studies were also reviewed to identify additional studies. Results: We identified 2,415 abstracts, of which 472 were selected for full text review. We identified 15 pharmacovigilance databases which reported adverse events attributed to yellow fever vaccination, of which 10 contributed data to this review with about 107,600,000 patients (allowing for overlapping time periods for the studies of the US VAERS database), and the data are very heavily weighted (94%) by the Brazilian database. The estimates of serious adverse events form three groups. The estimates for Australia were low at 0/210,656 for “severe neurological disease” and 1/210,656 for YEL-AVD, and also low for Brazil with 9 hypersensitivity events, 0.23 anaphylactic shock events, 0.84 neurologic syndrome events and 0.19 viscerotropic events cases/million doses. The five analyses of partly overlapping periods for the US VAERS database provide an estimate of 3.6/cases per million YEL-AND in one analysis and 7.8 in another, and 3.1 YEL-AVD in one analysis and 3.9 in another. The estimates for the UK used only the inclusive term of “serious adverse events” not further classified into YEL-And or YEL-AND and reported 34 “serious adverse events.” The Swiss database used the term “serious adverse events” and reported 7 such events (including 4 “neurologic reactions”) for a reporting rate of 25 “serious adverse events”/million doses. Conclusions: Reporting rates for serious adverse events following yellow fever vaccination are low. Differences in reporting rates may be due to differences in definitions, surveillance system organisation, methods of reporting cases, administration of YFV with other vaccines, incomplete information about denominators, time intervals for reporting events, the degree of passive reporting, access to diagnostic resources, and differences in time periods of reporting.

Background: With increased prevalence of extended spectrum beta-lactamase (ESBL) in hospital practice globally, reporting of extended spectrum beta-lactamase along with drug susceptibility test is expected from clinical microbiology laboratory. The aim was to evaluate cefoperazone and cefoperazone+sulbactum disc for phenotypic detection of extended spectrum beta-lactamase among E. coli and Klebsiella spp. isolates. Methodology: A total of 948 clinical specimens were analysed which included 496 E. coli and 392 Klebsiella pneumoniae. For confirmation of extended spectrum beta-lactamase ceftazidime/ceftazidime+clavulanidc acid and cefotaxime/ cefotaxime+clavulanic acid discs were used as recommended by Clinical Laboratory Standard Institute (CLSI). Simultaneously randomly selected 100 isolates, each of E. coli and Klebsiella spp. were identified for extended spectrum beta-lactamase genes coding for the TEM, SHV and CTX by polymerase chain reaction (PCR). The results were compared with cefoperazone/cefoperazone+sulbactum disc diffusion method. Result: Phenotypic characterization identified a high extended spectrum beta-lactamase rate. Four hundred out of 496 (80.64%) E. coli and 392 out of 452 Klebsiella spp.(86.7%) were positive for extended spectrum beta-lactamase by the Clinical Laboratory Standard Institute method. The increase in zone size of cefoprazone/cefoperazone+sulbactum (≥5mm) was seen for all the isolates of E. coli and Klebsiella spp. which were confirmed as extended spectrum beta-lactamase by Clinical Laboratory Standard Institute as well as polymerase chain reaction (PCR) method. Conclusion: cefoperazone/cefoperazone+sulbactum disc diffusion showed 100% concordance with extended spectrum beta-lactamase detection by ceftazidime/ ceftazidime+clavulanidc cefotaxime/cefotaxime+clavulanic acid disc diffusion method and polymerase chain reaction.

Opioid use in the management of chronic pain is widespread. However, it is a recognized risk factor for the development of osteoporosis. The hypothesis of this study was to evaluate the effect of various analgesic drugs; morphine, fentanyl and tramadol, on the bone of adult female rats. Forty rats were divided into 4 groups; Control, morphine (8 mg/kg), fentanyl (32 μg/kg) and tramadol (10 mg/kg) groups. After 90 days of treatment, the serum calcium, alkaline phosphatase, osteocalcin and estradiol were assayed and the bones were prepared for histomorphometric study. In comparison to the control group, morphine and fentanyl groups showed a significant biochemical and histological osteoporotic changes while treatment with tramadol leads to non-significant osteoporotic effect. In conclusion, tramadol had the least osteoporotic effect as compared to morphine or fentanyl on chronic administration suggesting the safety use of tramadol in the treatment of patients with chronic pain particularly in association with osteoporosis.

Clozapine is the best treatment option in several clinical circumstances, including treatment-resistant schizophrenia, non treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. However, clozapine is associated with many serious side effects. Furthermore, monitoring requirements, i.e., frequent blood draws and frequent visits, discourage clozapine use. Therefore, the drug is underused. The only way to avoid the underuse of clozapine is full awareness of its side effects and competence to minimize them. The aim of the paper is reviewing the safety profile of clozapine and the suggested strategies in the management of its side effects, including neutropenia, eosinophilia, seizures, myocarditis, weight gain, diabetes, metabolic syndrome, hypersalivation, fever, constipation, ileus, urinary incontinence, sweating. The neuropsychiatric side effects of clozapine are not discussed in this review.

Vinorelbine (VRN) is one of the most representative compounds of its class: the vinca alkaloids. VRN interferes with microtubule assembly. VRN shows a better therapeutic index than the parent compound vincristine and vinblastine probably because of its higher affinity for mitotic microtubules. VNR high affinity for mitotic microtubules causes a high clinical efficacy for the treatment of non-small cell lung cancer (NSCLC) and for breast cancer (BC), together with a good tolerability at therapeutically effective doses. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for VRN. The antitumor activity of VNR is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, VNR may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. The VNR is also characterized by improved hematologic tolerance and less neurotoxicity compared to parent compound. The aim of this review is 1) to explore the efficacy and tolerability of VNR in cancer therapy and 2) to examine the more recent approaches to improve the efficacy and tolerability of VNR in cancer therapy.

The current case describes an interesting event in a male patient in which detumescence of an ischemic priapism was obtained following an inadvertent intra-cavernosal injection of fentanyl mistaken for phenylephrine. Detumescence was achieved after injecting a total of 4.0 mls. Patient tolerated the procedure well and his vital signs were stable throughout the entire process. The possible causes of such an outcome as well as the miscommunication that has lead to such an injection are discussed.

Methotrexate (MTX) therapy may be effective in patients with rheumatoid arthritis (RA) or psoriasis due to its anti-inflammatory and immunosuppressive properties. Potential liver toxicity of MTX exists, but the incidence of MTX- specific lesions in liver biopsy of patients with RA and elevated serum transaminase levels is rare; however, severe hepatic damage may occurs unexpectedly in these patients. We describe the first documented case of an adult patient with RA who developed an acute flare of severe hepatitis after long-term therapy with MTX. Autoantibodies positivity, elevated serum IgG levels and compatible liver biopsy findings prompted us to diagnose autoimmune hepatitis, most probably triggered by a breakdown of immune tolerance induced by MTX. A complete remission was achieved in this patient with corticosteroids therapy.

Interruption of oral anticoagulation is discussed often, particularly in the outpatient setting. We present a 66- year-old woman who developed a thrombus in the left atrial appendage under bridging therapy with fondaparinux. With this case report we would like to emphasize that off-label use of fondaparinux should not be administered to patients at high risk for systemic embolism

Magnesium homeostasis is essential for many intracellular processes and depends on dynamic interplay of intestinal absorption, exchange with the bone reservoir, and renal excretion. Hypomagnesaemia may arise from various disorders. We review the case of a 59 year-old man whose only complaint was irritability with a routine analysis showing hypomagnesaemia and hypokalemia while using esomeprazole, a proton pump inhibitor (PPI). Fractional magnesium excretion was low, excluding excessive renal loss. Potassium excretion was 80 mEq/24 Hr in the presence of hypokalemia suggesting hypomagnesaemia-induced kaliuresis as its cause. Hypomagnesaemia partially resolved after oral magnesium supplementation. Esomeprazol suppression corrected hypomagnesaemia. A causal relationship with esomeprazol use was supported by the recurrence of hypomagnesaemia after rechallenge. We review the literature on hypomagnesaemia due to the use of proton pump inhibitors. In the past decade our understanding of transcellular magnesium transport was enhanced by the discovery of the magnesium channel, transient receptor potential (TR PM) 6 and 7 and other proteins that play an important role in its transport. In this light we discuss the possible etiology of proton pump inhibitor related hypomagnesaemia/hypokalemia

There is increasing concern about the development of diabetes mellitus and associated complications in patients administrating second-generation antipsychotics. Previous reports indicate that the risk of quetiapine, although relatively lower, is not negligible. We report a patient with bipolar disorder who, after treating with low-dose quetiapine, develops newly-onset diabetes and hyperglycemic hyperosmolar state. Clinical manifestations and managements of quetiapine associated diabetes are addressed, and we recommend routine monitoring of serum glucose after initiating quetiapine treatment at any given dose.