Current Drug Safety - Volume 11, Issue 2, 2016

Counterfeit drugs are a worldwide concern. This organized crime has deterrent effect on public health and on pharmaceutical business across the globe. Lack of comprehensive standardized definition of counterfeit drugs with global acceptance, higher benefits of cost ratio and intercomplexity of market and globalized network are the major reasons behind this. Unawareness among the stakeholders lack of intellectual property protection and social-economic factor also resulted in flourished market of fake drugs. Despite of several attempts made by global regulatory agencies, inefficient regulations, lax enforcement of existing legislation and lack of commitment by involved authorities still remain major loopholes, aggravating the serious problem of counterfeiting. Although use of techniques based on interference pattern, encryption, spectroscopy and chromatographic principles by pharmaceutical industries to authenticate genuine products has curtailed the problem to a limited extent. In order to efficiently control the organized crime of medicine counterfeiting, collective efforts of ‘National Counterfeit Control Agencies’, pharmaceutical industries, law regulatory agencies and public are essential. Strict legal enforcement, applications of comprehensive database, interlinked network and technological advancement are need of the hour. The purpose of this article is to overview all aspects of drug counterfeiting including current status and magnitude, effectiveness and limitation of existing technologies available to counter with particular attention to suggest possible roadmap to overcome the problem through uni-directional and focus global co-operation.

Background: Selective Serotonin Reuptake Inhibitors (SSRIs) have become the mainstay of treatment for depression, anxiety, and many other conditions. However, they have been associated with an increased risk of hyponatremia. Little is known about the risk of SSRI-associated hyponatremia in certain potentially at-risk populations, such as patients with acute medical illnesses. Objective: The main objective of this study was to examine the effect of SSRIs on serum sodium levels in medically-ill inpatients. Method: We performed a retrospective cohort study of 239 medically-ill inpatients assessed by the psychiatric consultation-liaison team of a large Canadian academic hospital between 2008 and 2014. We grouped patients based on whether they were exposed to an SSRI, a non-SSRI antidepressant, or no antidepressant at all. Our primary outcome was the maximum decrease in serum sodium level observed within 30 days of antidepressant exposure in the inpatient setting. Our secondary outcome was the incidence of hyponatremia (serum sodium level <135 mEq/L) or severe hyponatremia (sodium level <130 mEq/L) within the same time frame. Results: The maximum decrease in sodium serum level from baseline did not differ between the 3 groups studied (SSRIs - 3.31 mEq/L vs non-SSRI antidepressants -3.41 mEq/L vs no antidepressants -3.13 mEq/L, F (2) = 0.79, p= 0.92). The incidence of hyponatremia and severe hyponatremia did not differ between groups either. This remained the case after controlling for covariates. Conclusion: SSRIs do not appear to be associated with an increased risk of hyponatremia in medically-ill inpatients. Clinicians should not avoid prescribing SSRIs in this population based solely on the assumption of hyponatremia risk.

This systematic review estimated the incidence of ADRs that lead to hospitalization (ADRAd) and that developed during hospitalization (ADRIn) and factors affecting in Indian population. Two independent investigators searched the electronic databases describing ADRs. Due to high heterogeneity, incidence of ADRAd and ADRIn were presented as median (interquartile range-IQR). We performed the subgroup analysis of incidence based on characteristics of the included studies. The meta-analysis (generic inverse variance method with random effect model) was possible for the fatal ADR incidence. The risk factors for ADRs were also explored from the included studies. We used ‘Review manager software version 5.0’ and ‘Graph Pad Prism version 6.0’ for the analysis. Of 77 fully evaluated references, 21 prospective studies were selected. The median incidence of ADRAd and ADRIn were 2.85% (IOR: 1.25 - 3.93%) and 6.34% (IQR: 3.36 - 16.37%), respectively. The subgroup analysis found high incidence rate with studies conducted in intensive care units, elderly age groups, with intensive monitoring, duration of > 1 year and multidisciplinary team. The fatal ADR incidence was 0.08% (95% CI: 0.00-0.15%). Important risk factors for ADRs included elderly, female sex and polypharmacy. The hospitalized patients have a significant burden of ADRs. The multiple factors may have affected their occurrence.

There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. Key Points: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

Introduction: Worldwide, iron deficiency anemia is the most common nutritional disorder. Treatment with oral iron supplementation may not be well tolerated due to gastrointestinal side effects. Therapy with Intravenous (IV) iron supplementation is more effective and better tolerated, especially in patients with underlying Inflammatory Bowel Disease (IBD) or malignancy. However, Hypersensitivity Reactions (HSR) and anaphylaxis to IV iron have been described. Methods: We evaluated the literature and developed an eleven step desensitization protocol for ferric carboxymaltose to be administered in high risk patients. Results: We present the first case series demonstrating the safety of ferric carboxymaltose desensitization in patients with a history of anaphylaxis to IV iron and iron deficiency anemia. Conclusion: While there are many IV iron formulations available, ferric carboxymaltose can replenish iron stores with fewer doses. Ferric carboxymaltose is contraindicated in patients with prior hypersensitivity reactions to iron formulations. This novel eleven step desensitization protocol was well tolerated without any adverse reactions and allowed the patients to receive iron supplementation when limited therapeutic options existed.

Background: Warfarin is the most widely prescribed oral anticoagulant frequently encountered in the patients presenting for both elective and emergent surgery. Maintaining therapeutic levels of warfarin therapy may increase the risk of blood loss and procedural complications, including complications from neuraxial and regional anesthetic techniques. However, in some vulnerable patient groups, discontinuing therapy may result in negative thromboembolic consequences. Objective: To review the published guidelines and supporting data from clinical studies addressing the safe and coordinated management of patients on warfarin therapy who present for perioperative care. Method: This review highlights the most up-to-date research from clinical trials as well as from retrospective studies in addition to multidisciplinary consensus guidelines regarding the safety of warfarin therapy and reversal in the perioperative period. Results: Based on the most up-to-date literature, certain patient groups may be more vulnerable to cessation of warfarin therapy before surgery and there exists a risk stratification algorithm. In many other cases, particularly emergent surgery, it may be necessary to reverse warfarin therapy preoperatively. There are anesthetic, surgical and safety implications in these clinical decision points. Conclusion: With the aging of the United States population, the prevalence of preoperative patients therapeutic on warfarin will continue to increase, necessitating the multidisciplinary and coordinated care of perioperative clinicians to ensure patient safety and optimize clinical outcomes.

Aim: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population. Methods: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs. Results: As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate. Conclusion: Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

Introduction: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease. Patients and Methods: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months. The severity of ADR was assessed using Hartwig Siegel scale and causality by Naranjo and WHO UMC Scale. Preventability was assessed using Schumock and Thornton scale and other parameters such as incidence, onset, duration, management and outcome were also assessed. Risk factors were assessed by bi-variate logistic regression analysis and length of hospital stay by T test. Results: The incidence of ADR was 10.42% in medicine wards. The causality of ADR done by Naranjo scale showed that most of the ADRs were probable (7.38%). Anti-tubercular agents were the leading cause of ADR. Duration of hospitalization was significantly longer (7.18 ± 2.64 vs. 5.06 ± 2.13 days) in patients with ADR (Odds ratio 1.38, 95% Confidence interval 1.26 to 1.51). 7.28% of ADRs were moderately severe. Seriousness criteria assessment showed that 0.33% were serious reactions. Most of the ADRs were definitely preventable. Most of the ADRs were managed by discontinuing the suspected drug. The present study showed female gender predominance over males for ADRs and no relationship with age. Conclusion: Adverse drug reactions impose significant burden on hospitals through prolonging patient stay and by increasing admission rates. The occurrence of ADR in this study was higher when compared to that reported in previous studies. This study highlights the importance of ADR reporting among ADR reporting among health care professionals in hospital.

Restless legs syndrome is an underdiagnosed sensori-motor disorder and psychotropic drugs are one of the main secondary causes of the illness. The most common psychotropic agents that cause restless legs syndrome are antidepressants; however, antipsychotics have also been reported to induce restless legs syndrome. The prevalence, vulnerability factors and the underlying mechanism of antipsychotic-induced restless legs syndrome are unclear. A possible explanation is that dopaminergic blockade is the main precipitator of the syndrome. Quetiapine-induced restless legs syndrome is another point of interest because of its low binding to D2 receptors. We herein report the case of a restless legs syndrome that emerged after a single low dose quetiapine administration.

Eltrombopag is a non-peptide thrombopoietin receptor agonist. Eltrombopag has originally been developed for conditions where therapy for thrombocytopenia is needed. Secondary to eltrombopag have been reported thrombotic events, chest pain, acute renal failure, neutropenia, ascites, retinal exudates, antiphospholipid syndrome. In this case, we present a 53 year-old patient who had diagnosis of Idiopathic Thrombocytopenic Purpura (ITP) for 30 years with splenectomy. He’s still having low thrombocyte counts despite the classical ITP therapy. He was treated with eltrombopag for the last 2 months and had inferior myocardial infarction despite that having no additional risk factors for coronary heart disease.

Treatment guidelines recommend omega-3 with Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) content not above 85% in patients with high plasma levels of triglycerides. Since the different up to date formulation of omega-3 available in commerce must be similar to clinical efficacy and safety, herein, we report the case a 52-year-old woman who presented clinical inefficacy using Olevia® omega-3 treatment. Clinical evaluation excluded the presence of intestinal or systemic diseases able to reduce the drug absorption. Switching the therapy from (Olevia®) to an equivalent omega-3 formulation (Esapent®), we documented a decrease in her plasma triglycerides levels. In order to evaluate a possible difference between these formulations we performed a single blind in vitro dissolution test using three pills for each formulation of omega-3 (Olevia®, Esapent® and another one chosen between the several formulations available in commerce: DOC Generic®) that revealed a significant difference (>20%) in the dissolution time of three different omega- 3 commercially available drug formulation.

Metabolic acidosis is one of the common manifestations of Isoniazid toxicity but rare with normally used doses of the drug. Among anti tubercular drugs, rifampicin, streptomycin and capreomycin are commonly implicated in renal injury. Here we report the first case of metabolic acidosis and renal injury caused by isoniazid at normal prescribed dose.

Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in “100% natural” or “herbal” supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated “Chinese herbal” supplement “Tiger King” for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was “possible” and “probable” respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient’s clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of “Tiger king” in particular, and other counterfeit medications or herbal supplements of unknown origin.

Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. It has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. We will now present the case of a 45-year-old woman who developed tics that involved the entire left side of her body after her dose of lamotrigine was increased from 200 mg daily (2.0 mg/kg/day) to 225 mg daily (2.3 mg/kg/day). We will review the prior cases of lamotrigine induced tics, and compare them to the circumstances surrounding our patient. We will also discuss the neurobiology of tics and make suggestions to improve the tics, based on the reported cases.

An 18 years old female patient, who was taking treatment for tinea cruris developed Toxic Epidermal Necrolysis (TEN) due to therapeutic dose of griseofulvin with concomitant use of terbinafine. Both the drugs were stopped; patient’s condition was gradually improved after starting the treatment. As per WHO-UMC causality assessment criteria, association between reaction and drug was possible (for both griseofulvin and terbinafine). Griseofulvin and terbinafine, both are widely used as an oral antifungal agent to treat fungal infections, careful monitoring is required in the initial periods of the treatment to prevent such type of serious adverse drug reaction. We report a case of TEN possibly caused by griseofulvin with concomitant use of terbinafine resulting in diagnostic difficulty.