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RIPER PDIC Bulletin (ISPOR India – Andhra Pradesh Chapter Newsletter)

1 May-June, 2013, Volume 4, Issue 33 [ISSN 2230-8741]

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RIPER PDIC Bulletin Also known as

ISPOR India – Andhra Pradesh Chapter Newsletter Indexed in ISPOR India- Andhra Pradesh Chapter, Pharmainfo.net, New Jour, Open J-Gate,

Ulrichsweb Global Serials Directory & HINARI, WHO

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R I P E R P o i s o n & D r u g I n f o r m a t i o n C e n t e r ( P D I C ) , R D T H O S P I T A L , B a t h a l a p a l l i , A . P . & R a g h a v e n d r a I n s t i t u t e o f P h a r m a c e u t i c a l

E d u c a t i o n a n d R e s e a r c h ( R I P E R )

O f f i c i a l p u b l i c a t i o n o f R I P E R & I S P O R I n d i a - A n d h r a P r a d e s h C h a p t e r



RIPER PDIC Bulletin

R I P E R P o i s o n & D r u g I n f o r m a t i o n C e n t e r ( P D I C ) ,

R D T H O S P I T A L , B a t h a l a p a l l i , A . P. &

Raghavendra Institute of Pharmaceutical Education and Research (RIPER)

I S P O R I n d i a – A n d h r a P r a d e s h C h a p t e r

Volume 4, Issue 33

May-June 2013

Editorial team Page 03

Contents Page 05

Editorial Page 06

Articles Page 07

Drug news 8

Instruction to authors Page 29

‘RIPER’ is the premier educational institution promoted by Raghavendra Educational & Rural

Development Society. The institution is established in 2002 under the leadership of four pharmacy

graduates including Dr. Y. Padmanabha Reddy and Dr. J. Ravindra Reddy. Now the institution is

offering; M. Pharm, B. Pharm, D. Pharm, Pharm D and PharmD (PB) courses approved by AICTE, PCI

and Govt. of AP. The college is affiliated to JNT University, Anantapur (JNTUA) / SBTET, AP.



EDITORIAL BOARD Chief editor Dr. Y. Padmanabha Reddy, Principal, RIPER & President, ISPOR India - Andhra Pradesh Chapter Editor Mr. Dixon Thomas, Head, Dept. of Pharmacy Practice, RIPER & President-elect, ISPOR India - Andhra Pradesh Chapter AssociAte editors Dr. Adepu Ramesh, Professor, JSS University, Mysore Dr. Gerardo Alvarez-Uria, Head, Dept. of Infectious Diseases, RDT Hospital Dr. P. Selvam, Research Director & Professor, RIPER Dr. C. Sowmya, Professor, RIPER Dr. P. Ramalingam, Professor, RIPER Dr. Jyothi MV, Professor, RIPER Mrs. Seeba Zachariah, Assoc Professor, RIPER, Secretary, ISPOR AP Chapter Dr. S. Sriram, Professor, SRIPMS, Coimbatore Dr. Roger Walker, Chief Pharmaceutical Officer, Wales, U.K. Dr. Chris Wisniewski, MUSC Drug Information Center, USA Ms. Atefa Noorain, Associate Research analyst, Thomson Reuters, Hyderabad Editorial advisory Board Dr. M.S. Kannan, Medical Director, RDT Hospital & Director, ISPOR AP Chapter Dr. A.N. Nagappa, Professor, Manipal University, Karnataka Dr. G.P. Mohanta, Professor, Annamalai Univeristy, T.N. Dr. Gayathri Palat, Program Director, Palliative Access (PAX) Programme, India Dr. C. Vijaya Raghavan, Vice-Principal, PSG College of Pharmacy, T.N. Dr. Subhash C. Mandal, Vice President, IPA-Bengal Branch Dr. Sunil K Jain, Chief Pharmacist, AIIMS, New Delhi Dr. B. J. Mahendra Kumar, Prof, JDT Islam College of Pharmacy, Kerala Dr. Gunasakaran, Clinical Head, Azidus Laboratory Ltd, T.N. Dr. S.S. Rao, Pharmacist, Canada Mr. Ali Dulfikkar, Pharmacist, Dubai Prof. M.N. Femi Oyewo, Olabisi Onabanjo University, Nigeria Dr. Ugochi Nyere Ogudu, Lagos Island Maternity Hospital, Nigeria Dr. Azubike Okwor, President, Pharmaceutical Association of Nigeria Dr. Cheikh Saad, Univeristy of Thies, Senegal Dr. Stein Lyftingsmo, Pharmacist, Norway Dr. M.K. Unnikrishnan, Professor, Manipal University, Karnataka Mr. Sonal Sekhar, Sr. Lecturer, Manipal University, Karnataka Dr. Hari Hara Nadha Sarma, Medical Superintendent, RDT Hospital, Bathalapalli Dr. H. Harish, Head, Dept. of Anesthesia RDT Hospital, Bathalapalli Dr. Tadepalli Durgesh, Head, Children’s Hospital, RDT Hospital, Bathalapalli Dr. K. Sudheer Kumar, Head, Dept. of Surgery, RDT Hospital, Bathalapalli Dr. Alexander Daniel Sunad, Surgeon, RDT Hospital & Director, ISPOR AP Chapter Mr. K. Thejomoorthy, Chief Pharmacist, RDT Hospital Mr. Prasanth Kumar, Data Manager, Novartis Healthcare Pvt. Ltd. Mr. Tapan Kumar Shah, Clinical Operations, Boehringer Ingelheim India Pvt. Ltd Dr. Baghavan PS, Registrar, Karnataka Pharmacy Council Dr. Tarun Wadhwa, Asst Professor, KLE College of Pharmacy, Belgaum



PUBLICATION & PROGRAM COMMITTEE Chairman Dr. J. Ravindra Reddy, Correspondent, RIPER

Director of the ISPOR AP chapter Mr. Vigneshwaran, Asst Prof, RIPER

Scientific Coordinators Mr. G. Narayana, Asst Prof, RIPER Dr. Mohan Raj, Asst Prof, RIPER Y Samhitha Reddy T Rajavardhana

ISPOR India – Andhra Pradesh Chapter membership managers Umesh Venkatesh Lokesh R N. Jagadeesh

Logistics Avaneendra Reddy

Regulatory News Bharghav Reddy Lakshmikanth Tippu Sulthan

Proof Reading & language editing K. Balaji, Asst Professor, RIPER M Bhavani Abdul Salam

Conference Proceedings & News S Rubiya B Sahithi

Indexing & Distribution Mr. M. Jaffar, Asst Professor, RIPER KR Venkatesh

ISPOR Advisors Nancy Sun Zandra Yin

Conference registration & documentation M Maneesh Kumar Reddy B Sahithi

Chapter advisors Dr. N Udupa Dr. AN Nagappa

Website Administration K Umesh

Resource persons Simu Thomas Azmi Burhani Denny John Subhodh K

RIPER PDIC Bulletin

Raghavendra Institute of Pharmaceutical Education and Research (RIPER) Chiyyedu Post, Anantapur 515721, AP, India Phone: 91-8978541693 [email protected], www.riper.ac.in, http://sites.google.com/site/riperpdicbulletin/,

http://www.ispor.org/regional_chapters/India-Andhra-Pradesh/index.asp Notice: For healthcare professionals only. View of authors are independent to that of editorial team, it is highly advised for consulting other drug information sources also for your specific needs. Publisher, editorial team or authors are not responsible for any damage happens due to the information provided. RIPER PDIC Bulletin Published by the Principal, RIPER, Anantapur— 515721, A.P



RIPER PDIC Bulletin

Contents

1 Editorial Page 06

2 Reimbursement decision-making and health

technology assessment: bridging the gap in non-core

pharmaceutical markets-Dávid Dankó

Page 07

3 Oral anticoagulants: a review of the newer agents

available for use in clinical practice-Alison Martin

Page 12

4 Aspirin use updates-Bhupinder Singh Sekhon Page 18

5 The menace of spurious drugs-RS Thakur Page 21

6 Effect of exposure to organophosphate pesticides in

the children of agricultural workers in rural India-

Neelam D Sukhsohale, Prachi R Sawant, Sushama S Thakre

& Sanjay B Agrawal

Page 23

7 Drug news Page 28

8 Instruction to the authors Page 29



Editorial

The proposed HealthNETIndia International Society for Pharmacoeconomics and Outcomes Research (ISPOR) is becoming more active in India. Now the society is developing ISPOR India Network and shortly there will be national PEOR guidelines. The proposed name for the network is HealthNETIndia. The mission of HealthNETIndia is the same as that of ISPOR, to increase the efficiency, effectiveness, and fairness of health care to improve health. The HealthNETIndia aims to:

Promote the awareness and the use of PEOR in India through the activities of the chapters in India Network.

Provide guidance and useful information in the development of health policy in India.

Support researchers and decision-makers by establishing resources and training courses on the research, tools, techniques, and methods.

Create opportunities to share knowledge and ideas by connecting Indian PEOR colleagues in and outside India.

Provide a platform for ISPOR to grow and expand its chapter activities in India. Those who are interested to join in HealthNETIndia could send a brief resume to [email protected] Sincerely yours, Dr. Y Padmanabha Reddy, M.Pharm, PhD, FIC President, ISPOR India-Andhra Pradesh Chapter Principal, RIPER & Chief Editor, RIPER PDIC Bulletin [email protected] In this issue, HTA and more… In this issue we have a good narration about health technology assessment (HTA) in non-core pharmaceutical markets by Dávid Dankó of Corvinus University of Budapest, Hungary. I hope this article will be of high use for Indian health care policy makers in reforming health technology assessment in India. There are also articles on oral anticoagulants, aspirin update, spurious drugs, and organophosphate poisoning in children. In addition, the drug news gives couple of updates; most important of them is of course, the ban of dextropropoxyphene for human use. Hope you enjoy reading variety of these write-ups. Best Regards, Mr. Dixon Thomas, M.Pharm, M.S., M.Sc. President-elect, the ISPOR, India-Andhra Pradesh Chapter HOD, Pharmacy Practice, RIPER & Editor, RIPER PDIC Bulletin, [email protected] [email protected]



Reimbursement decision-making and health technology assessment: bridging the gap in non-core pharmaceutical markets

Dávid Dankó

Research leader, Corvinus University of Budapest, Hungary Managing partner, Ideas & Solutions, Budapest, Hungary Introduction In many non-core pharmaceutical markets, there is a clear gap between health technology assessment (HTA) and pharmaceutical reimbursement decision-making processes. The nature of this gap can be basically twofold: either HTA is not used, or HTA and actual reimbursement decisions are only tangentially aligned. In this essay, I set out to explore the potential reasons of this discrepancy, and I endeavour to give some recommendations on how HTA could come closer to reimbursement decision-makers (payers) and offer them effective support. The thoughts below try to synthesize my previous experiences in a payer role (when I was responsible for pharmaceutical reimbursement in Hungary, a middle-income European Union member state), as well as insights from university research and my market access advisory activities. Economic evaluation as the mainstream of HTA in non-core pharmaceutical markets Health technology assessment (HTA) includes all methodologies and processes for the systematic evaluation of pharmaceutical products and other health technologies (e.g. medical devices, surgical procedures, public health programmes) linked to pricing & reimbursement decisions by public and private payers, preceding to admission to the formulary and during formulary management. The broad nature of this definition is crucial, as we sometimes tend

to reduce HTA to cost-effectiveness analysis (CEA) and budget impact analysis (BIA). Indeed, these two techniques—which we may call together as ‘economic evaluation’—have until recently constituted the mainstream of thought within health technology assessment. This stream originates from academic institutions in the United Kingdom and is currently hallmarked by England’s National Institute of Clinical Excellence (NICE) as well as the Scottish Medicines Consortium (SMC). This approach has been implemented, for example, in South Korea, Poland and Hungary. Today, CEA and BIA—which we may call together as ‘economic evaluation’—increasingly constitute only one stream of thought within health technology assessment. Equally important is ‘qualitative assessment’, which usually refers to techniques where the assessment logic is similar to that of regulatory agencies. In many of these approaches, a scoring system is used and the outcome is the classification of the health technology into one of several (typically 4-5) categories based on therapeutic value added. France, Italy, Japan and Taiwan are examples for this approach. The third main paradigm is what we may call ‘balanced assessment’. This covers methodologies and systems which aim at integrating the strengths of the previous two approaches, offering a balanced (i.e. not too quantitative, not too qualitative, thus unbiased) perspective on medical



technologies (cf. Exhibit 1). Traditionally, Australia and Canada have been seen as countries with balanced assessment, albeit with different methodology focuses. Currently we can already see a convergence between economic

evaluation and qualitative assessment in other markets: France has adopted cost-effectiveness analysis, Sweden uses a kind of a societal approach, and the UK is clearly steering away from mainstream economic evaluation.

Exhibit 1. Three paradigms of health technology assessment

(PL – Poland, HU – Hungary, UK – United Kingdom, KS – South Korea, F – France, I – Italy, J – Japan, TW – Taiwan / Republic of China, CAN – Canada, AUS – Australia, CH – Switzerland, S – Sweden) In those non-cost pharmaceutical markets, where HTA already exists, economic evaluation is still dominant. The reason is mainly institutional: for example, in Central Europe, HTA was conceptualized between 2001 and 2005. When the first Central European scholars brought health technology assessment concepts into Poland, Czech Republic and Hungary, they established contacts primarily with UK universities with health economics focus, and had access to English-language health economics literature. These tended to teem with the mainstream concepts of that time: cost-effectiveness analyses, QALY and ICER. Such ideas—which offered a huge step forward in non-core pharmaceutical

markets compared to the pre-HTA age when non-transparent and over-politicized decision-making was the norm—became the guiding principle for HTA thinking. With local HTA landscapes being heavily influenced by the pioneering health economics scholars, knowledge transfers subsequently took a markedly technocratic trend, and the more pragmatic qualitative paradigm found difficulty in gaining any foothold. This is why most non-core pharmaceutical markets are still in an earlier stage of the ‘economic evaluation lifecycle’ (cf. Exhibit 2), compared to core markets, and this is also why qualitative drug assessment has remained largely unknown and undocumented up to now.



Exhibit 2. The ‘economic evaluation’ lifecycle

The HTA gap On the other hand, there are signs that payers are increasingly disappointed with economic evaluation both in core and non-core pharmaceutical markets. Some core-EU countries are in phase 4 of the economic evaluation lifecycle, while others have already stepped into phase 5. For those non-core pharmaceutical markets, which are now in the process of public debate on HTA implementation (e.g. South-East Asia), these instances of disappointment carry crucial pieces of information. In order to understand these,

let’s consider the typical flow of the reimbursement decision-making process (cf. Exhibit 3) in an ‘average’ non-core market. First, it is readily visible that there is no such person as ‘payer’; instead, there are many payers at several different layers, and most of them lack the methodology-heavy health economics expertise which could enable them to interpret economic evaluations. What is more, most of them can never realistically be expected to master even those HTA skills which are seen as basic by health economists.

Exhibit 3.Stakeholders in ‘payer role’ along the reimbursement decision-making process



Second, in most non-core markets, budget pressure and the degree of politicization in reimbursement policy shift actual decisions up to ministerial (or sometimes even higher) levels, where the analytical nature of economic evaluation often turns out to be outright irrelevant for decision-makers who are mostly intuitive. Third, budget pressure leads even analytical decision-makers to zoom in on budget impact exclusively, which introduces a large—and dysfunctional—bias into how economic evaluation is applied and interpreted. Fourth, although economic evaluation does not disregard broader clinical, societal and ethical impacts perse, its mere endeavour to condense cost-effectiveness information into one almighty ratio (ICER – incremental cost-effectiveness ratio, i.e. the cost of buying one more quality-adjusted life year) diverts attention away from clinical and societal factors to quantitative, i.e. financial aspects. Fifth, the significant academic uncertainties behind QALY-assessment tend to undermine the legitimacy of economic evaluation with those payers who take the time to dig into technicalities. Sixth and finally, economic evaluation can be disproportionately costly in non-core pharmaceutical markets, because of the infrastructural need it has on the authorities’ side and difficult to implement, as necessary capabilities are missing in part or in total. To take a simple example: an average HTA agency which carries out primary assessments is said to need at least 30-50 experts to ensure operational continuity and decision consistency. There are not so many trained and qualified experts in the smaller countries, and even if human resources were available, financials still would not be enough to employ so many civil servants for drug assessment.

These anomalies are already visible in everyday practice in some non-core markets: for example, those Central European countries which apply HTA in their reimbursement decision-making processes (Poland and Hungary have separate HTA agencies; Czech Republic, Slovakia and Slovenia perform such evaluations without having set up any dedicated agency) have recently experienced either a public backlash of pro-HTA policies or a loss of influence of health technology assessment. In the meantime, in those countries where there is no institutionalized HTA, there is an ever widening gap between scholars arguing for economic evaluation and pharmaceutical and government decision-makers looking for pragmatic solutions. Bridging the gap It is highly likely that many non-core pharmaceutical markets cannot, or do not want to, afford the investment need to establish full-scale HTA agencies. It is also clear that those stakeholders who are involved in reimbursement decision-making are—to put it mildly—unenthusiastic about detailed analytical information. What they need is quick and pragmatic answers to their questions (and doubts) regarding the therapeutic value and cost-effectiveness of new drugs, and an algorithm to prioritise completely different products across various therapy areas when there are not enough resources to reimburse all of them. For this purpose, balanced assessment based on an ‘ultra-light HTA agency model’ may be more appropriate, cost-saving and realistic than implementing economic evaluation. In this model, an independent government agency is established which directly reports to the Ministry of Health or, alternatively, to the



Prime Minister. This agency—which can be set up with as few as 5-10 experts—itself does not carry out either economic evaluation or request economic models to be submitted by manufacturers. Instead, it gathers the transferable elements of appraisals from a selected number of agencies carrying out economic evaluation (e.g. NICE, SMC, PBAC, CADTH) and relies on the guidance that they have provided. At the same time, it adds its own independent assessment covering budget impact (affordability) and 4-5 qualitative criteria such as unmet need, side effect profile, and comparative improvement in key clinical indicators, eventually public health policy priorities and accessibility in other middle-income countries. Thus, the agency is able to provide a quick balanced assessment of all new pharmaceuticals within a reasonable timeframe, and at reasonable costs. The assessment should be provided either as a scorecard (with numerical weights) or an unambiguous verbal statement providing clear and understandable normative guidance for decision-makers. The guidance may refer to the reimbursability, reimbursement rate and/or price, depending on the structure of national reimbursement systems. Idealistically, subsequent decisions themselves are taken not by individual ministries or

payers, but by a collective body (committee) in which all stakeholders of the otherwise chaotic reimbursement process (shown in Exhibit 3) are represented at the same table. This ‘pragmatic balanced assessment’ (PBA) model may provide an implementable and resource-saving way of launching health technology assessment in non-core pharmaceutical markets where HTA capabilities still need to be reinforced and HTA-related costs cannot be high. The main criticism against this model can be that it legitimates ‘free-riding’ on technology assessments carried out by rich countries and that local cost and utility values are disregarded. Although there is some truth in these criticisms, the ethical issues related to ‘free-riding’ can be managed via bilateral agreements, while re-assessing cost-effectiveness with cost values in countries where non-drug costs (e.g. health care salaries) are unsustainably low seems a questionable practice itself. Thus, I believe that balanced assessment based on ultra-light HTA agency may be a pragmatic approach which brings HTA into effective reimbursement decision-making processes in non-core pharmaceutical markets.



Oral anticoagulants: a review of the newer agents available for use in clinical practice

Alison Martin PharmD candidate, South Carolina College of Pharmacy Class of 2013, USA

For many years, warfarin (Coumadin®), a vitamin K antagonist (VKA), was the only oral anticoagulant available in the United States for the long-term prevention of various venous and arterial thromboembolic events. Although warfarin has been shown to be highly effective, many practical complications often limit its use in clinical practice. Along with its narrow therapeutic index, warfarin use is further complicated by its slow onset of action, multiple drug and food interactions, and requirement of frequent laboratory monitoring to evaluate both efficacy and safety. In response to this need for newer agents that were equally effective but more convenient, 3 new oral anticoagulants have recently been developed and approved for use by the Food and Drug Administration (FDA).1 Dabigatran etexilate (Pradaxa®), rivaroxaban (Xarelto®), and apixaban (Eliquis®) exert their anticoagulant effects via different mechanisms than warfarin, though all work to prevent thrombus formation. One of the primary advantages of these agents over warfarin is the use of fixed-dose regimens without the need for frequent laboratory monitoring of coagulation parameters. In recent years, multiple clinical trials have been conducted to study the efficacy and safety of these agents for multiple indications, including stroke prevention in atrial fibrillation (AF), treatment and prevention of venous thromboembolism (VTE), and prevention of ischemic events in acute coronary syndromes (ACS). This review will briefly summarize key aspects of

landmark clinical trials conducted and provide a comparison of these newer medications. Pharmacokinetic parameters and other drug characteristics are compiled in Table 1. Dabigatran (Pradaxa®) Dabigatran was the first of the 3 new oral anticoagulants to be approved by the FDA.2 Classified as a direct thrombin inhibitor (DTI), dabigatran inhibits both free and clot-bound thrombin in addition to thrombin-induced platelet aggregation. Currently, dabigatran is indicated only for use in patients with nonvalvular AF to reduce the risk of stroke and systemic embolism. Standard regimens include twice daily dosing, with dose reductions recommended in renal impairment. Dabigatran should be dispensed in its original container to maintain stability; capsules remain stable up to 4 months once the container is opened. Compared with other oral anticoagulants, dabigatran has been associated with higher rates of dyspepsia, likely due to the tartaric acid content. Another safety concern unique to dabigatran includes a possible increase in the risk of ACS, though whether this is due solely to dabigatran use has been debated.3 The clinical trial leading to FDA approval of dabigatran, the RE-LY study, evaluated the rates of stroke or systemic embolism. Fixed doses of dabigatran, at either 110 or 150 mg twice daily, were compared with adjusted-dose warfarin [target international normalized ratio (INR) of 2 to 3] in patients with



nonvalvular AF at increased risk of stroke. Significantly lower rates of stroke and systemic embolism were seen in patients receiving the 150 mg dose of dabigatran, along with similar rates of major bleeding when compared with warfarin. Risk reduction in the group receiving the lower dabigatran dose compared with warfarin did not reach statistical significance, though lower rates of major hemorrhage were demonstrated. Patients who were at an increased overall bleeding risk were those 80 years of age and older and those with renal impairment.4

Dabigatran has also been evaluated recently for use in valvular AF. The RE-ALIGN trial was a phase II study initiated to compare dabigatran with warfarin for stroke prevention in AF patients with mechanical valves.5 This trial was terminated early due to an increase in strokes, myocardial infarctions, and other major thrombotic events, in addition to an increase in major bleeding, seen in patients randomized to receive dabigatran over those in the warfarin treatment arm. Subsequently, the FDA has released a statement informing health care professionals that dabigatran should not be used in patients with mechanical prosthetic heart valves.6 Rivaroxaban (Xarelto®) The first of 2 new factor Xa inhibitors to be approved was rivaroxaban. As opposed to dabigatran and apixaban, rivaroxaban has gained approval for several indications including stroke and systemic embolism in nonvalvular AF, treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), and DVT prophylaxis following hip or knee replacement surgery.7Rivaroxaban is also the only new oral anticoagulant with a fixed once-daily dosing regimen, which may be advantageous in noncompliant patients.

Dosing adjustments are required in renal impairment, and use should potentially be avoided in severe liver impairment or with the concomitant use of rivaroxaban with combined P-glycoprotein (P-gp) and strong cytochrome P450 (CYP) 3A4 inhibitors. Efficacy and safety of rivaroxaban was compared with warfarin in the ROCKET-AF study, where patients with nonvalvular AF were randomized to receive either rivaroxaban 20 mg daily or dose-adjusted warfarin (target INR of 2 to 3) in a double-blind, double-dummy fashion. The primary efficacy composite endpoint was time to first event of stroke or systemic embolism. Major and non-major clinically relevant bleeding was also assessed. Rivaroxaban demonstrated non-inferiority to warfarin for the prevention of stroke or systemic embolism in the intention-to-treat population. Investigators noted that when analyzing the efficacy in the as-treated population, rivaroxaban was superior to warfarin. Rates of major and non-major bleeding were also similar between the two groups, with some subtle differences in other specific bleeding episodes, shown in Table 2.8 Other landmark clinical trials comparing rivaroxaban with conventional therapy have been conducted that ultimately led to FDA approval of additional indications for use. Rivaroxaban was compared with dose-adjusted VKA bridged with enoxaparin for the treatment and secondary prevention of DVT or PE in the EINSTEIN-DVT and EINSTEIN-PE studies, respectively.9-10 For the primary efficacy endpoints, composites of time to first occurrence or recurrence of DVT or PE, rivaroxaban was found to be non-inferior to enoxaparin-bridged VKA. The EINSTEIN-extension study evaluated the further risk reduction in recurrence of DVT and PE with



prolonged rivaroxaban treatment, compared with placebo, after patients received either VKA or rivaroxaban for 6 to 12 months following the initial event.11

Rivaroxaban demonstrated superiority for the primary efficacy endpoint of incidence of symptomatic recurrent VTE, defined as the composite of recurrent DVT, nonfatal PE, or fatal PE. Additionally, a series of 4 studies, known as the RECORD trials, compared rivaroxaban with enoxaparin for prophylaxis of DVT following hip or knee arthroplasty. Both total VTE and major VTE, defined as proximal DVT, nonfatal PE, or VTE-related death, were significantly reduced in the rivaroxaban group.12-15 Apixaban (Eliquis®) Similar to rivaroxaban, apixaban, the newest oral anticoagulant to be approved by the FDA, is an oral factor Xa inhibitor. Currently, apixaban is only indicated for use in non-valvular AF to reduce the risk of stroke and systemic embolism. A fixed twice-daily dose is indicated in most patients, though dose reductions are recommended for certain patients, as outlined in Table 1.16 Dose reductions may also be required with concomitant use of apixaban and inhibitors of both CYP3A4 and P-gp, as co-administration can increase apixaban concentrations and thus bleeding risk. Efficacy and safety of apixaban was evaluated in 2 landmark trials. Apixaban was first directly compared with aspirin in the AVERROES trial, in which nonvalvular AF patients were not candidates for warfarin.17 This trial was terminated early after a significant reduction in stroke and systemic embolism was seen with apixaban over aspirin at the interim analysis. A modest increase in rates of major and minor bleeds was seen in the apixaban group, though these were not significantly

different from rates seen with aspirin. Apixaban was then directly compared with dose-adjusted warfarin (target INR of 2 to 3) in the ARISTOTLE trial.18 The risk of stroke and systemic embolism was evaluated in patients with nonvalvular AF who were randomized to treatment. Apixaban was shown to be superior to warfarin for reducing the risk of stroke and systemic embolism, which was driven primarily by a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion. A significant reduction in all-cause death was also seen with apixaban. The primary safety endpoint of major bleeding was significantly lower with apixaban than with warfarin. Furthermore, apixaban demonstrated a significantly lower bleeding risk than warfarin in all other bleeding endpoints except gastrointestinal bleeding, in which there was no significant difference between the two agents. Comparison of Oral Anticoagulants Given the lack of head-to-head comparator trials, several meta-analyses and indirect comparisons of these newer agents have recently been performed in attempts to determine which medication may provide the best overall net clinical benefit. Two indirect comparisons have recently been made incorporating data from the RE-LY, ROCKET-AF, and ARISTOTLE clinical trials, as each evaluated similar primary efficacy and safety endpoints. Patient characteristics were most similar in the RE-LY and ARISTOTLE trials, whereas in ROCKET-AF, warfarin-treated patients had a lower mean time in therapeutic range and overall stroke risk was higher than the other two trials, as depicted below in Table 2. Lip and colleagues demonstrated a significantly lower risk of stroke and systemic embolism with dabigatran over rivaroxaban, whereas no differences were



seen when apixaban was compared with either rivaroxaban or dabigatran. Major bleeding rates, however, were significantly lower with apixaban when compared with both agents.3 Similar results were also seen in the indirect comparison performed by Baker et al.19

Collectively, the new oral anticoagulants were associated with a lower risk of stroke or systemic embolism, hemorrhagic stroke, and all-cause mortality than warfarin in addition to lower rates of major bleeding.3,19 When compared with the traditional VKA used in clinical practice, these newer agents offer several potential advantages. Given the lower degree of variability in anticoagulation response, fixed-dose regimens can be utilized and laboratory monitoring of coagulation parameters are not routinely required, providing a more convenient therapeutic alternative. Clinical trials have demonstrated that these agents are either

non-inferior or superior to warfarin in preventing major thromboembolic events. In fact, the CHEST guidelines now recommend dabigatran as first-line treatment for stroke prevention in those AF patients with a CHADS2 score of 1 or greater.20 However, one must consider several factors when deciding the most appropriate anticoagulant therapy in each patient; specifically, the likelihood of medication compliance, other concomitant medications and their potential drug interactions, degree of renal dysfunction, risk of bleeding, and insurance status. Another important consideration is the lack of reversal agent available for the newer anticoagulants, whereas vitamin K may be used to reverse the actions of warfarin. As with any other therapeutic decision, the entire patient must be viewed as a whole in order for the clinician to choose the most appropriate course of treatment and to provide the best quality of patient care.

Table 1. Key Characteristics and Pharmacokinetic Parameters of New Oral Anticoagulants

Dabigatran (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

MOA Direct Thrombin Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Dose

150 mg BID 75 mg BID if CrCl 15-29 Do not use if CrCl< 15

20 mg daily 15 mg daily if CrCl 15-50

5 mg BID 2.5 mg BID if 2 of: age 80 years, weight 60 kg, SCr 1.5 mg/dL

Bioavailability 3-7% 66% 50% Half-life 12-17 hr 5-9 hr 12 hr Time to peak 1 hr 2-4 hr 3-4 hr Effect of food Delayed onset with high fat

meal, no effect on bioavailability

Take with food to increase bioavailability

No effect on bioavailability

Protein Binding 35% 92-95% (albumin) 87% Metabolism P-glycoprotein (P-gp) CYP3A4/5 CYP3A4/5 and P-gp Excretion Renal (80%) Renal (66%) Renal (27%) Monitoring Not required; aPTT Not required; aPTT,

antifactorXa Not required; aPTT, antifactorXa

Antidote NA; dialyzable NA NA NA, none available



Table 2. Summary of Clinical Trials Comparing New Oral Anticoagulants with Warfarin

Dabigatran Rivaroxaban Apixaban Clinical Trial RE-LY ROCKET-AF ARISTOTLE Stroke Reduction vs. Warfarin

Superior

Non-inferior

Superior

Bleeding Risk vs. Warfarin

No difference in major bleeds; ICH, critical and fatal bleeding, major and minor bleeding; GI bleeds

No difference in major bleeds; ICH, critical and fatal bleeding; GI bleeds, bleeding requiring transfusion, Hgb decrease 2 g/dL

major bleeds, severe or serious bleeding, ICH, any bleeding; no difference in GI bleeds

Mean CHADS2 2.1 3.5 2.1 Mean Warfarin TTR 64% 55% 62% Converting from Warfarin

D/C W and start D when INR < 2

D/C W and start R when INR < 3

D/C W and start A when INR < 2

Converting to Warfarin

CrCl 50: start W 3 d before d/c D; CrCl 30-50: 2 d before CrCl 15-30: 1 d before

No clinical trial data; R affects INR; D/C R and start parenteral anticoagulant with W at next scheduled dose

No clinical trial data; A affects INR; D/C A and start parenteral anticoagulant with W at next scheduled dose

ICH, intracranial hemorrhage; Hgb, hemoglobin; GI, gastrointestinal; D/C, discontinue; W, warfarin; D, dabigatran; R, rivaroxaban; A, apixaban; TTR, time in therapeutic range (defined as INR = 2.0 – 3.0); CHADS2 Score, index of stroke risk in patients with AF (defined as congestive heart failure,

hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack)

References 1. Perez A, Eraso LH, Merli GJ.

Implications of new anticoagulants in primary practice. Int J ClinPract. 2013;67:139-156.

2. Product information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral capsules. BoehringerIngelheim Pharmaceuticals, Inc, Ridgefield, CT, 2010.

3. Lip GYH, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibriallation. J Am CollCardiol. 2012;60:738-46.

4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Investigators. Dabigatran versus warfarin in

patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

5. Van de Werf F, Brueckman M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J. 2012;163:931-7.e1.

6. FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. Safety announcement 19 December 2012. Available at: http://www.fda.gov/Drugs/DrugSa



fety/ucm332912.htm (accessed 17 January 2013).

7. Product Information: XARELTO(R) oral tablets, rivaroxaban oral tablets. Janssen Pharmaceuticals, Inc., Titusville, NJ, 2011.

8. Patel MR, Mahaffey KW, Garg J. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91.

9. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-510.

10. The EISTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-97.

11. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomative venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev CardiovascTher. 2011;9:841-4

12. Eriksson BI, Borris LD, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008; 358:2765-75.

13. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind randomised controlled trial. Lancet. 2008;372:31-9

14. Lasen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-86

15. Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-80.

16. Product Information: ELIQUIS(R) oral tablets, apixaban oral tablets. Bristol-Myers Squibb, Princeton, NJ, 2012.

17. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.

18. The ARISTOTLE Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.

19. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. CircCardiovascQual Outcomes. 2012;5:711-9.

20. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9thed: American College of Chest Physicians evidence-based clinical practice guidelines. CHEST. 2012;141(2_suppl):e44S-e88S.



Aspirin use updates

Bhupinder Singh Sekhon Faculty of Pharmaceutical Sciences, PCTE Institute of Pharmacy, near Baddowal Cantt., Ludhiana-142 021, India Aspirin (Formula: C9H8O4, Molecular Mass: 180.1574) has been around for over a century and is one of the oldest, simplest, cheapest, most pervasive, and one of the most widely used medicine in the world: 100 billion (109) aspirin pills, weighing 400,000 t, are swallowed yearly on Earth and in the space stations.1,2 It is one of very few old drugs still used today.3 It is a nonsteroidal anti-inflammatory drug and further classified as a salicylate. There are different formulations available for aspirin. Acetylsalicylic acid is the generic name of aspirin and there are many brand names. Aspirin is available as a regular tablet, extended-release tablet, enteric-coated tablet, delayed-release tablet (i.e., medication is released some time after it is taken), chewable tablet, gum, and suppositories. It also can be an ingredient in a combination drug.

Aspirin is still the first line of therapy for patients with unstable angina or non-ST-elevation myocardial infarction and should be administered as soon as possible after hospital presentation and maintained indefinitely as long as tolerated.4 Aspirin helps keep blood clots from forming on the surface of ruptured atherosclerotic plaques. Non-coated aspirin acts within minutes of ingestion to stop platelets from forming blood clots. Enteric-coated aspirin takes longer to work but acts just as quickly as uncoated aspirin if chewed. Today, robust data supports that low-dose aspirin (up to 150 mg a day) has potential benefit in terms of reducing the risk of heart attack and stroke, and can be beneficial to individuals who already have experienced a heart

attack, stroke, angina or peripheral vascular disease, or have had certain procedures such as angioplasty or bypass. Aspirin acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins and thus reduce pain and swelling. Researchers found conflicting recommendations in various guidelines about the use of aspirin for the primary prevention of cardiovascular events. In general, the use of aspirin seems no longer justifiable in primary prevention in patients with or without diabetes.5 However; the researchers also warned that excessive use of aspirin can have some unwanted effects such as bleeding in the gut and ulcers.6

Based on the analysis of medical

data of 25,000 patients collected over many years, it was observed that taking aspirin for at least five years lowered the risk of several types of cancer, including those of the lung, prostate, breast, colon, esophagus, stomach, colon, bladder, kidney, gall bladder, and brain. Aspirin works specifically on the platelets, preventing them from aggregating7 and the arteries of heart are less likely to go into spasm, shutting off blood flow. A low dose of aspirin may block the growth and spread of breast cancer by preventing the creation of resistant cells that drive the disease.

Although substantial evidence

from randomized trials confirms benefit from aspirin in the secondary reduction of vascular disease but there is debate about its use in primary prevention. Experts are



of the opinion that it is important that in considering the risk–benefit balance of aspirin prophylaxis from a public health point of view, reductions in vascular disease events and in cancer are considered together. Furthermore, low-dose aspirin is considered prophylaxis and not treatment, and so advice about aspirin should be given to subjects within the context of a healthy lifestyle which enable them to make informed decisions about the protection of their own health.8 Furthermore, the net benefit of aspirin in prevention of cardiovascular disease and nonvascular events remains unclear.9 Aspirin can also act against miscarriages.10

Macular degeneration also called ‘age-related macular degeneration’ is a leading cause of blindness in older people. It is a major cause of visual impairment in adults over the age of 50 – making it difficult or impossible to read or recognize faces. Recent studies showed that people who regularly take aspirin for many years, such as those with heart problems, are more likely to develop a form of blindness, and are independent of a history of cardiovascular disease and smoking.11 However, people taking aspirin for heart and stroke prevention benefits should not be alarmed, nor should they stop their aspirin regimens without first consulting their doctors. Further research is needed to clarify and investigate some of the issues raised in this concern.11

The incidence of Alzheimer’s

disease rises exponentially with age and its prevalence will increase significantly worldwide in the next few decades. Inflammatory processes have been suspected in the pathogenesis of Alzheimer’s disease. Studies have shown that aspirin has a preventive action only and needs to be taken before the symptoms of Alzheimer’s disease set in.

However, aspirin cannot be recommended for the treatment of Alzheimer’s disease.12

Aspirin use in Alzheimer’s disease

might pose an increased risk of intracranial hemorrhage whereas it has no effect on cognition.13 Studies provide evidence that taking aspirin in low doses may be an effective way to promote brain functioning for women who are at risk of heart disease.14

Aspirin, Buffered With Ca/Al/Mg

Antacid - Oral (Brand name(s)- Ascriptin, Bufferin) product is a combination of aspirin and an antacid (such as calcium carbonate, aluminum hydroxide, or magnesium oxide and is used to treat headache, toothache, menstrual pain, and minor aches and pains caused by arthritis or the common cold. The antacids in this combination medicine help reduce heartburn or stomach discomfort caused by the aspirin contained in the medicine. It may also be used to reduce pain and swelling in conditions such as arthritis.

The history of aspirin is

experiencing a second youth, and the range of its applications is constantly expanding.15 References 1. Zundorf LU. 100 Years of Aspirin:

The future has just begun. Bayer AG. 1997.

2. Vainio H, Morgan G. Aspirin for the second hundred years: new uses for an old drug. Pharmacol Toxicol. 1997; 81:151–152.

3. Fuster V, Sweeny JM. Aspirin. A historical and contemporary therapeutic overview. Circulation. 2011;123:768-778.



4. Jneid H et al. 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non- ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. July 16, 2012.

5. Matthys F, De Backer T, De Backer G, Stichele RV. Review of guidelines on primary prevention of cardiovascular disease with aspirin: how much evidence is needed to turn a tanker?. Eur J Prev Cardiol. December 20, 2012.

6. Mirror, Aspirin, http://www.mirror.co.uk/news/uk-news/aspirin-key-fight-against-breast-1846453.

7. Martindale, The Extra Pharmacopoeia, 30th ed, p5.

8. Elwood PC, Mustafa M, Almonte M, Morgan G. The risks and benefits of prophylactic aspirin in vascular disease and cancer. Clin Investig (Lond) 2012;2(12):1177-1184.

9. Rao R, Seshasai K, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, Ray KK, Effect of aspirin on vascular and nonvascular outcomes meta-analysis of randomized controlled

trials FREE. Arch Intern Med. 2012;172(3):209-216.

10. Telegraph, http://www.telegraph.co.uk/health/healthnews/9630434/Aspirin-could-prevent-thousands-of-miscarriages-leading-doctor.html, 25 Oct 2012.

11. Liew G, Mitchell P, Wong TY, Rochtchina E, Wang JJ. The association of aspirin use with age-related macular degeneration. JAMA Intern Med. 2013;173(4):258-264.

12. Jaturapatporn D, Isaac MG, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2012;2: CD006378.

13. Thoonsen H, Richard E, Bentham P, Gray R, van Geloven N, De Haa RJ, Van Gool WA, Nederkoorn PJ. Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage: cause for concern? Stroke. 2010 ;41(11):2690-2.

14. Hive health media, http://www.hivehealthmedia.com/study-aspirin-preserve-brain-function-women.

15. Dodziuk H; Exciting Aspirin, 08 January 2013; http://www.chemistryviews.org/details/ezine/4202261/Exciting_Aspirin.html.



The menace of spurious drugs

RS Thakur President, Federation of Indian Pharmacists Organizations “Islamabad (Anantnag),: A team of experts from Central Drugs Standards Control Organization recently visited various hospitals in South Kashmir and collected samples of many drugs as part of the investigation ordered by Union Health Ministry into the spurious drug scam in Kashmir. Official sources” Courtesy: Greater Kashmir e-Newspaper The precipitating issues related to quality of drugs in hospitals of Kashmir are highly deplorable. Such incidences are often reported in press in others parts of India too, but hardly any permanent measure is taken to solve it once forever. The root cause of this problem lays in the fact that pharmacy services are not given due importance and status in health care system of India. As the doctor is expert in diagnosis and treatment of disease, so is pharmacist expert in checking and maintaining the quality of drugs. Ironically, in India pharmacy services is put on back burner. In the purchase planning, drug product selection, and procurement pharmacists are not involved at all. Directorate of Pharmacy is not established in Health Department, which is a must to ensure quality medicines supplied through our hospitals and dispensaries and quality of services rendered by pharmacists to the patients regarding safety and efficacy of drug products. Thus all technical aspects relating to ensuring the quality of drug product before it is purchased for hospital supply or for proper storage and preservation of procured drugs to preserve and maintain their quality and potency till it is used by the patient are

completely overlooked at the cost of public health. The first and foremost issue in relation to handling procurement of drugs is that it cannot be treated as any other item of commerce or commodity of day to day use. Drugs are two edged weapon, which can both cure or kill. Right use of right drug in right dose at right time through right route of administration to the right patient can save precious life, whereas, a substandard drug product, be it misbranded, adulterated or spurious, may not only fail in giving any relief to the patient but may be toxic too, lead to new complications and fatal effects. History of medicine is full of such misadventures and it is the disasters from medicines that lead to stringent regulatory measures in form of Drugs Act. As long as this vital difference between drug and other commodities is not fully appreciated and Pharmacists are not solely involved in all aspects relating to drugs and pharmaceuticals any attempt to curb the menace shall remain futile and dangers posed by spurious drugs on public health shall loom large. The issues to be addressed are: Reorganizing Pharmacy Services both

at Center and in States. Establishing Directorate of Pharmacy

both at Center and in States. Establishing pharmacy and

therapeutics committee in all States and all major hospitals.

Preparation of hospital formulary for the States/major hospitals.



Selecting drug products only after sample quality assessment of past several batches to assure quality.

Prequalification inspection of manufacturing facility.

Prequalification inspection of in-house testing facilities.

Regular analysis of each batch of supply in two different laboratories under neutral label with bar coding to discourage supply of substandard products.

Lowest quotation cannot be criteria for purchase of drug products.

Proper storage infrastructure for each product as per storage condition prescribed for the product in Schedule P of Drugs and Cosmetics Rules, 1945 or in the Pharmacopoeia is a must both during transportation as well as storage and distribution.

Availability of testing facilities within the State for all drug products which are purchased for hospital supply is a must.

A dynamic quality monitoring system and clinical evaluation of product efficacy to be set up.

All Medical Colleges and Pharmacy Colleges to set up quality control laboratory for random analysis and testing of drugs procured for hospital supply.

Establishment of pharmacovigilance facility to generate data of drug related problems in patients.

Establishment of pharmacoeconomics facility for rationalizing medication cost and efficient utilization of hospital budget.

Streamlining payment system. For addressing all these issues and fixing accountability it’s essential that Directorate of Pharmacy is set up in the Health Department to man and manage every issue related to drugs and pharmaceuticals for hospital supply and ensure that best quality medicines are made available at all times. This will, not only reduce cost but also reduce burden on hospital beds and OPD cases, because it will reduce drug induced diseases and drug related toxicities which prevail between 7 to 9% on an average and they affect vital organs like liver, kidney, pancreas, gall bladder, lungs etc and substantially affect quality of life and thus productive man hours. It is high time to reorganize pharmacy services both at Centre and in the States and ensure safe and effective medication to all, thus a healthy India. World Health Organization states “Pharmacist disseminates information on the safety and efficacy of pharmaceutical products.” Let it be implemented in letter and spirit for a better health.



Effect of exposure to organophosphate pesticides in the children of agricultural workers in rural India

Neelam D Sukhsohale, Prachi R Sawant, Sushama S Thakre & Sanjay B Agrawal

Department of Preventive and Social Medicine, Indira Gandhi Government Medical College, Nagpur, India

Abstract Background and objectives: Children of agricultural families in rural areas of developing countries like India appears to have a high potential for pesticide exposure, particularly when their parents are engaged in activities such as pesticide mixing, application, and intensive hand labor in treated fields. The present study was carried out with the objective of assessing the effect of exposure to organophosphate (OP) pesticides in children of agricultural workers in rural India. Methods: A community based cross-sectional study was carried out in 100 children aged 8-15 years [study group (n=50) exposed to OP pesticides and control group (n=50) not exposed to OP pesticides] in adjoining villages (Khedgaon, Mehunbare, Khedi khurd) of Taluka Chalisgaon, district Jalgaon, Maharashtra. Various neurological symptoms like muscarinic (diarrhea, urinary incontinence, lacrimation, excessive salivation), nicotinic (tremors, muscle weakness, tachycardia), and general symptoms (headache, insomnia, numbness in legs, fatigue, anorexia, nausea, vomiting, dizziness, lethargy) were assessed by a standard Q16 questionnaire. Results and Conclusions: The study group suffered more from muscarinic, nicotinic and general symptoms as compared to control group. On analysis, a statistically significant difference was found between study group and control group for muscarinic and general symptoms (p<0.05). It was also observed that with increase in exposure index, the symptoms (muscarinic, nicotinic and general) also increased in exposed study group. Thus high prevalence of neurologic symptoms found among the children of agricultural workers (exposed to OP pesticides) as compared to unexposed group could be attributed to cumulative exposure to OP pesticides. Key Words: Organophosphate (OP) pesticides, neurological symptoms, children of agriculture workers, rural Introduction Exposures to organophosphates are broadly classified into two categories: occupational and environmental. Occupational exposures occur among agricultural workers (including migrant farm workers), industrial workers, pest control exterminators, and other workers. Non-occupational exposure affects a large segment of the general population

worldwide. Residential exposures come from organophosphate pesticide use by exterminators and by household residents as well as from dietary and accidental exposures. Other environmental exposures occur in public places and areas close to farms, and exposures could also happen from organophosphate use in chemical warfare or terrorism.1, 2



Children living in agricultural areas of developing countries like India may be exposed to higher pesticide levels than other children because of pesticides tracked into their homes by household members, by pesticide drift, by breast milk from their farm worker mother, or by playing in nearby fields. Pesticides exposure is mainly toxic to the brain and may produce well-defined muscarinic, nicotinic, and cholinergic neuro-symptoms involving both central and peripheral nervous systems.3 Increases in both central and peripheral neurologic symptoms are also found in many studies on moderate exposure.4 With this background, the present study was carried out to study the effect of exposure to OP pesticides in children of agricultural workers in rural India. Methods A community based cross-sectional study was carried out in 100 children in the age group 8-15 years [study group (n=50) and control group (n=50)] in the adjoining villages (Khedgaon, Mehunbare, Khedi khurd) of Taluka Chalisgaon, district Jalgaon, Maharashtra during the year 2012. Selection of study group: 50 rural children in the age group of 8-15 years exposed to organophosphate pesticides were included. Selection of control group: 50 rural children in the age group of 8-15 years never involved in pesticide handling (neither outdoor nor indoor) belonging to similar socio-economic strata and have no family history of pesticide exposure were included. The study was approved by Institutional Ethics Committee. After obtaining written informed consent from the parents of children, various neurological symptoms like muscarinic

(diarrhea, urinary incontinence, lacrimation, excessive salivation), nicotinic (tremors, muscle weakness, tachycardia) and general symptoms like headache, insomnia, numbness in legs, fatigue, anorexia, nausea, vomiting, dizziness and lethargy were assessed. The questions on the symptoms were based on an established questionnaire Q16 that was used to evaluate the effects of occupational exposure to neurotoxicants by Lundberg et al.5 Exposure index (EI) was calculated by multiplying the number of hours exposed to organophosphate (OP) pesticides and the number of years of exposure. Children were categorized according to exposure index as < 1, 1- 4 and >4 hours per years of exposure. Also, detailed history regarding demographic variables, socioeconomic status, personal history and presenting complaints if any were inquired. In addition complete clinical examination including general and systemic examination was done. Statistical analysis: Data analyses (differences between categorical variables tested with chi-square test) were conducted by means of statistical software OpenEpi Info version 2.3 year 2009. P values less than 0.05 were considered as statistically significant.

Results

The study group suffered more from muscarinic, nicotinic and general symptoms as compared to control group. On applying 2 test, it was found that the presence of muscarinic symptoms and general symptoms in study group was significantly more than control group (p<0.05). However, no statistically significant difference was found between the study and control groups as far as the nicotinic symptoms are concerned (p>0.05). The findings are summarized in



Table 1. It was also observed that with increase in exposure index, the symptoms (muscarinic, nicotinic and general) also increased in exposed study group.

However, when 2 test was applied between exposure index < 4 and >4, the difference was not found to be significant (p>0.05) as shown in Table 2.

Table 1: Distribution of study subjects according to presence or absence of Muscarinic, Nicotinic and General Symptoms

Muscarinic Symptoms

Study group (n= 50) Control group (n = 50) 2 df 1 p value

Present 22 (44) 10 (20)

6.61 *0.01 Absent 28 (56) 40 (80)

Nicotinic symptoms

Present 19 (38) 22 (44)

0.37 0.54 Absent 31 (62) 28 (56)

General symptoms

Present 40 31

3.93 *0.04 Absent 10 19

Figures in parentheses indicate percentage. *statistically significant

Table 2: Distribution of study group (N=50) according to symptoms and exposure index.

Exposure index Muscarinic symptoms

Nicotinic symptoms

General symptoms

2 df 2 p value

<1 1 (2) 0 1 (2)

3.16 0.20 1 – 4 9 (18) 4 (8) 16 (32)

>4 12 (24) 15 (30) 23 (46)

Figures in parentheses indicate percentage.

Discussion

In the present study, we evaluated the role of exposure to

organophosphate (OP) pesticide exposure in the children of agricultural workers of rural areas in India. We found the high prevalence of muscarinic, nicotinic and



general symptoms in study group exposed to OP pesticides study group as compared to control group. It was also observed that the various symptoms increased with increase in exposure index. Our study findings conform to the findings of other investigators.6-8 The important neurologic manifestations in the form of muscarinic, nicotinic, and general symptoms may be attributable to the chronic effects of most of the OP pesticides on the peripheral and central nervous systems.9 The pesticide-related neurologic symptoms, both muscarinic and nicotinic observed in this study could be due to the inhibition of red blood cells, acetyl cholinesterase, as well as plasma butyryl cholinesterase recorded in the study group and reported in earlier studies by the authors.10,11 Lotti, observed that the association between OP pesticide exposure and neurotoxic effects are well known.12 Farhat et al. also studied the association between pesticide exposure and neurologic endpoints and concluded that environmental and occupational exposure to OP pesticides leads to neurodegenerative functions in agricultural workers.13 Studies on neurologic symptoms among Sri Lankan farmers showed that 24% of the neurologic symptoms resulted from occupational exposure to AChE-inhibiting OP insecticides.14 Thus we infer that the knowledge and understanding of neurological symptoms among exposed children of agricultural workers will be useful in creating awareness and imparting knowledge (regarding use of personal protective equipments, improved eye safety, hand washing, balanced diet) among agricultural workers of rural India. Conclusions

Thus high prevalence of neurologic symptoms found among the children of

agricultural workers (exposed to OP pesticides) as compared to unexposed group. Future studies are needed to find out ways to decrease exposure of OP pesticides to children. Acknowledgement Our sincere thanks to Indian Council of Medical Research (ICMR), for approving and granting conduct of this research. References

1. Jaga K, Dharmani C. Sources of exposure to and public health implications of organophosphate pesticides. Rev Panam Salud Publica. 2003;14(3):171-85.

2. Rastogi SK, Tripathi S, Ravishankar D. A study of neurological symptoms on exposure to organophosphate pesticides in the children of agricultural workers. Indian Journal of occupational and environmental medicine. 2010;14:54-57.

3. Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. Neurologic symptoms in licensed private pesticide applicators in the Agricultural Health Study. Environ Health Perspect. 2005;113:877-82.

4. Kamel F, Hoppin JA. Association of pesticides exposure with neurologic dysfunction and disease. Environ Health Perspect. 2004;112:950-8.

5. Lundberg I, Hogberg M. Evaluation of the Q16 questionnaire on neurotoxic symptoms and review of its use. Occup Environ Med. 1997;54:343–350.

6. Gomes J, Lloyd O, Revitt MD, Basha M. Morbidity among farm workers in a desert country in relation to long-term exposure to



pesticides. Scand J Work Environ Health. 1998;24:213-9.

7. Strong LL, Thompson B, Coronado GD, Griffith WC, Vigoren EM, Islas I. Health symptoms and exposure to organophosphate pesticides in farmworkers. Am J Ind Med. 2004;46:599-606.

8. Bazylewicz-Walczak B, Majczakowa W, Szymczak M. Behavioural effects of occupational exposure to organophosphorus pesticides in female greenhouse planting workers. Neurotoxicology. 1999;20:819-26.

9. Savitz DA, Sonnenfeld NL, Olshan AF. Review of epidemiologic studies of paternal occupational exposure and spontaneous abortions. Am J Ind. Med. 1994;25:361–83.

10. Rastogi SK, Singh VK, Kesavachandran C, Jyoti, Siddiqui MK, Mathur N, et al. Monitoring of plasma butyrylcholinesterase activity and hematological parameters in pesticide

sprayers. Indian J Occup Environ Med. 2008;12:29–32.

11. Rastogi SK, Satyanarayna PV, Ravishanker D, Tripathi S. A study on oxidative stress and anti-oxidant status of agricultural workers exposed to organophosphate insecticides during spraying. Indian J Occup Environ Med. 2009;13:131–4.

12. Lotti M. Experimental and clinical neurotoxicology. New York: Oxford University Press. 2000.p.911-8.

13. Farhat TM, Abdelrasoul GM, Amir MM, Shebi MM, Farhat FM, anger WK. Neurobehavioural effects among workers occupationally exposed to organophosphorus pesticides. Occup Environ Med. 2003;60:279-86.

14. Peiris-John RJ, Ruberu DK, Wickremasinghe AR, Smit LA, vander Hoek W. Effects of occupational exposure to organophosphate pesticides on nerve and neuromuscular function. J Occup Environ Med. 2002;44:352-7.



Drug News

Ban on Dextropropoxyphene for Human use Dextropropoxyphene is likely to involve risk to human beings and whereas safer alternatives to the said drugs are available; the Central Government suspend of manufacture, sale, and distribution of the drugs in the country in public interest by a notification released on May 23, 2013, in exercise of the powers conferred by section 26A of the Drugs and Cosmetic Act, 1940), with immediate effect. Reference: Drug Information Bulletin, IPA Bengal Branch, 2013; 7(12). Ranbaxy fine In a recent update from USFDA, Ranbaxy has to pay a fine of $500 million. In 2008, Daiichi-Sankyo, a Japanese company acquired Ranbaxy. The company was fined for manufacturing and distributing poor quality drugs for long time. As the issue had happened before Daiichi-Sankyo take over Ranbaxy, it could claim the previous owners in India to settle the fine. Reference: http://www.topnews.in/ranbaxy-can-be-forced-compensate-daiichi-fda-fine-2379655 Death following olanzapine pamoate injection? In a recent communication, the U.S. Food and Drug Administration (FDA) has been investigating two unexplained deaths in patients who received an intramuscular injection of the antipsychotic drug Zyprexa Relprevv (olanzapine pamoate). The patients died 3-4 days after receiving an appropriate dose of the drug, well after the 3-hour post-injection monitoring period required under the Zyprexa Relprevv Risk Evaluation and Mitigation Strategy (REMS). Both patients were found to have very high olanzapine blood

levels after death. High doses of olanzapine can cause delirium, cardiopulmonary arrest, cardiac arrhythmias, and reduced level of consciousness ranging from sedation to coma. Reference: http://www.fda.gov/Drugs/DrugSafety/ucm356971.htm Ketoconazole - Risk of Potentially Fatal Liver Toxicity Ketoconazole has been associated with rare cases of serious hepatotoxicity including liver failure and death. This risk was also observed in patients with no pre-existing liver disease and no serious underlying medical conditions. Hepatotoxicity and death have been reported to occur at recommended doses and with treatment courses longer than 10 days. The Warnings’ sections of the Product Monographs have been updated to include the following additional instructions: ketoconazole tablets are indicated for the treatment of serious or life threatening systemic fungal infections and should not be considered for mild to moderate infections. Oral ketoconazole has been associated with hepatic toxicity, including cases with fatal outcomes. Liver function tests should be performed in all patients before starting treatment, at week 2 and 4, and monthly thereafter. Treatment should be stopped if liver parameters are elevated (> 3 times the normal limit) or if patients develop clinical signs or symptoms consistent with liver disease such as anorexia, nausea, vomiting, jaundice, fatigue, abdominal pain, dark urine, or pale stools. Reference: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/34173a-eng.php



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