|Year : 2023 | Volume
| Issue : 1 | Page : 64-69
Drug Safety Alerts Issued by the National Coordination Centre for Pharmacovigilance Programme of India: Current Practices and Future Recommendations
Dasaraju Rajesh1, Muppala Thejaswini2
1 Department of Pharmacology, Chirayu Medical College and Hospital, Bhopal, Madhya Pradesh, India
2 Department of Biochemistry, Chirayu Medical College and Hospital, Bhopal, Madhya Pradesh, India
|Date of Submission||16-Jan-2023|
|Date of Decision||25-Feb-2023|
|Date of Acceptance||27-Feb-2023|
|Date of Web Publication||31-Mar-2023|
Department of Pharmacology, Chirayu Medical College and Hospital, Bhopal - 462 030, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Background: Adverse drug reactions (ADRs) due to drug therapy are inevitable and prior knowledge of their causative agents can avoid unnecessary economic burden on patients as well as on the health-care system. Objectives: To create awareness among health-care professionals about the drug safety alerts (DSAs) issued by the National Coordination Centre for Pharmacovigilance Programme of India (NCC-PvPI) till December 2022 and to reiterate the importance of spontaneous reporting of adverse events for better patient care. Methodology: A retrospective analysis of 141 DSAs issued from March 2016 to December 2022 was done. The ADRs were analyzed for the type of reactions, system organ class, and according to drug class. Microsoft Office 2007 was used to formulate the data and presented it in a descriptive manner using numbers and percentages. Results: Out of 141 DSAs under analysis, 101 individual drugs, 2 drug classes, and 7 drug combinations have developed 144 ADRs. These ADRs were compressed into 86 different types as similar ADRs were caused by more than one drug. Drug Reaction with Eosinophilia and Systemic Symptoms is the most common ADR noticed, followed by skin manifestations such as toxic epidermal necrolysis, acute generalized exanthematous pustulosis, skin hyperpigmentation, fixed drug eruption, symmetrical drug-related intertriginous and flexural exanthema, and photosensitivity reaction. The most common causative drugs for ADRs were antimicrobial agents, cephalosporins being the most commonly implicated medication class. Conclusions: Most of the ADRs advised to closely monitor by the NCC-PvPI through DSAs were treatable by early and appropriate management. Due to the high number of skin manifestations observed in the analysis, the role of dermatologists in taking detailed drug history is critical when making a differential diagnosis of skin lesions. Motivation and creating awareness among health-care professionals and patients to spontaneously report adverse events can only strengthen the pharmacovigilance system in India.
Keywords: Antimicrobials, drug safety alerts, National Coordination Centre for Pharmacovigilance Programme of India, skin manifestations
|How to cite this article:|
Rajesh D, Thejaswini M. Drug Safety Alerts Issued by the National Coordination Centre for Pharmacovigilance Programme of India: Current Practices and Future Recommendations. Asian J Pharm Res Health Care 2023;15:64-9
|How to cite this URL:|
Rajesh D, Thejaswini M. Drug Safety Alerts Issued by the National Coordination Centre for Pharmacovigilance Programme of India: Current Practices and Future Recommendations. Asian J Pharm Res Health Care [serial online] 2023 [cited 2023 Jun 8];15:64-9. Available from: http://www.ajprhc.com/text.asp?2023/15/1/64/373374
| Introduction|| |
An adverse drug reaction (ADR) is defined by the World Health Organization (WHO) as “any noxious, unintended or undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis or therapy.” The risk of ADRs increases with the use of multiple drugs (polypharmacy), types of medications, disease complexity, and comorbidities. Advancing age and genetic variability also influence susceptibility to develop ADRs.
Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem. To monitor drug safety, the WHO started a Programme for International Drug Monitoring in 1968 on a pilot basis involving 10 countries with established national reporting systems for ADRs. Since then, the network has expanded significantly with the number of countries participating in the program reached to 175. India joined the mission in July 2010, with a nationwide ADR monitoring program called the PV Programme of India (PvPI).
Starting with 22 ADR monitoring centers (AMCs) in 2010, PvPI has expanded in leaps and bounds with the help of more than 650 AMCs spread across the country. This is visible in terms of the number of individual case safety reports (ICSRs) being received (15729 in 2011 to 70915 in 2021) by the national coordination centre (NCC) through its VigiFlow software. Through the training programs and interactive sessions at the level of health-care institutions and pharmaceutical companies, PvPI is thriving hard to develop skilled human resources to report quality ICSRs by following good PV practices guidelines.
The PvPI has started issuing monthly drug safety alerts (DSAs) from March 2016 onward to advise health-care professionals and patients/consumers to closely monitor the possibility of the ADRs mentioned in the DSAs when prescribing/consuming these drugs. The PvPI has also started celebrating national PV week across the country from 17th to 23rd September every year starting 2021 onward to increase awareness among all the stakeholders involved in medicine use for the treatment of diseases about the reporting of adverse events and its importance.
Thorough knowledge of ADRs with their causative agents is essential for the treating physician for optimal treatment and better outcomes. Hence, this study attempted to create awareness among health-care professionals about the ADRs mentioned in the DSAs issued by the NCC-PvPI till December 2022 and also to reiterate the importance of spontaneous reporting of adverse events for the safe use of medicines.
| Methodology|| |
A retrospective observational study was conducted to analyze the DSAs issued by the NCC-PvPI, under the Ministry of Health and Family Welfare, Government of India, from March 2016 to December 2022.
The data regarding ADRs were collected from the DSAs available freely to the public in the online database of the Indian Pharmacopoeia Commission (IPC). The ADRs were analyzed for the type of reactions, system organ class, and according to drug class.
Microsoft Office 2007 version 12 (USA) was used to formulate the data and presented it in a descriptive manner using numbers and percentages.
| Results|| |
Our analysis showed that 141 DSAs issued by the IPC from March 2016 to December 2022 comprise 144 ADRs. Out of 144 ADRs, Drug Reaction with Eosinophilia and Systemic Symptoms is the most common ADR noticed, followed by toxic epidermal necrolysis, acute generalized exanthematous pustulosis, skin hyperpigmentation, fixed drug eruption, symmetrical drug-related intertriginous and flexural exanthema, photosensitivity reaction, alopecia, tinnitus, vasculitis, etc., [Table 1].
|Table 1: Types of adverse drug reactions suggested through drug safety alerts to monitor (2016-2022)|
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By considering that some drugs were responsible for causing the same type of ADRs, the total number of ADRs accounts for 86 only. Skin manifestations (24) were the most common ADRs caused by drugs, followed by gastrointestinal disorders (12), nervous system disorders (8), cardiovascular disorders (8), and musculoskeletal disorders (7). [Figure 1] depicts the system organ class of ADRs.
|Figure 1: System organ class of ADRs (n = 86). ADRs: Adverse drug reactions|
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A total of 101 individual drugs, 2 drug classes (cephalosporins, sodium-glucose co-transporter 2 inhibitors), and 7 drug combinations were implicated in the causation of 144 ADRs. Drugs more frequently associated with ADRs were antibacterials, followed by drugs used for cardiovascular system (CVS) and central nervous system (CNS) disorders, respectively. Among the antibacterials, cephalosporins were the most commonly implicated medication class. Overall, the majority of ADRs were reported by antimicrobials. Looking at the drug combinations, the interaction between quetiapine and valproic acid caused the highest number of ADRs followed by the drug combination of piperacillin and tazobactam [Table 2].
|Table 2: Drug classes involved in the causation of adverse drug reaction|
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| Discussion|| |
To the best of our knowledge, this is the first study analyzing the DSAs issued by the IPC since their inception. It was observed that the majority of the ADRs advised to closely monitor by the NCC-PvPI belong to “skin and subcutaneous tissue disorders,” followed by “gastrointestinal disorders,” “CNS disorders,” and “cardiovascular disorders.” Skin manifestations were the most common ADRs in the largest survey studies conducted in Portugal and Zimbabwe., In addition, in the same studies, it was observed that the drugs more frequently associated with ADRs were antimicrobials, which resonates with the findings of our analysis.
On the contrary, the largest cumulative evaluation of spontaneous reports from the German database revealed that the drugs used for the treatment of nervous system disorders were most commonly associated with ADRs. Cardiovascular drugs were found to be the most common drug class implicated in ADRs in the UK and US due to the increased prevalence of cardiovascular disorders among their population., However, a global study concluded that the usage of antimicrobials was associated with more ADRs in low-income countries compared to high-income countries. This could be due to the irrational use of antimicrobials in developing countries that lack stringent regulations to dispense them.
Interactions between the drugs were also implicated in the causation of ADRs. Drug interactions can occur via several mechanisms. A large number of important interactions are pharmacokinetic and occur due to changes in the rates of drug metabolism brought about by other medicines that are inducers or inhibitors of drug metabolism. Evidence from previous studies indicates that the probability of ADRs when two drugs are taken is estimated at 6%, increases to 50% when five drugs are taken, and becomes 100% when eight or more drugs are taken simultaneously. Though the recognition of every potential drug interaction is a challenge to the treating physician, efforts to reduce inappropriate polypharmacy should be made in patients suffering from chronic ailments such as hypertension, diabetes, asthma, and cancer, to prevent unexpected adverse effects.
The advantages of the PV system are many. It ensures pharmaceutical companies follow good manufacturing practices during clinical trials as well as after the drug is approved for marketing purposes. It also provides valuable information on the drug activity in vulnerable patients like elderly and pregnant women who may not be allowed to participate in actively controlled clinical trials due to consent issues. The number of people who receive the drug in a clinical trial will be relatively small in number and the drug under investigation is tested for a limited period, so additional reactions will likely happen after the drug is approved to use in a large number of patients, for a longer period and with other medicines. Postmarketing Drug Safety Surveillance is the only way to get an accurate picture of the drug's safety and ensure adverse events are properly reported for review, for instance through the NCC-PvPI's established adverse event reporting mechanisms. Based on the NCC-PvPI recommendations, Central Drugs Standard Control Organization took 26 regulatory actions till 2020 in the form of directing the manufacturers of the drug implicated in the causation of adverse reaction to incorporate the ADR in the package insert of the drug being marketed in the country.
Similar to other developing countries, the practice of ADR monitoring and PV in India has made great progress in the past 10 years. However, underreporting is a major drawback in India from all the stakeholders, especially health-care professionals. Therefore, more efforts are needed to motivate and create awareness among health-care professionals and patients to spontaneously report adverse events to strengthen the PV system in India for the safe use of medicines.
| Conclusions|| |
Most of the ADRs advised to closely monitor by the NCC-PvPI through DSAs were treatable by early and appropriate management. Physicians of all specialties and particularly those managing patients with infectious diseases, psychiatric disorders (schizophrenia, depression, etc.), epilepsy, and hypertension must inspect the possibility of adverse reactions associated with the use of suspected drugs. Due to the high number of skin manifestations observed in the analysis, the role of dermatologists in taking detailed drug history is critical when making a differential diagnosis of skin lesions.
The lack of information on the causal relationship of adverse reaction with the drug is a major limitation of DSAs as they were issued by the NCC-PvPI after a detailed assessment of the causality, severity, predictability, and preventability of ADRs using various criteria such as the WHO–Uppsala Monitoring Centre system, Naranjo Probability Scale, modified Hartwig and Siegel scale, Rawlins and Thompson criterion, and modified Schumock and Thornton scale. Given this information in the DSAs might help the treating physician to take rational decisions in disease management.
Adverse reactions like fixed drug eruption and genital pruritus due to cephalosporins and sodium-glucose co-transporter -2 inhibitors, respectively, were considered class effects in the DSAs in our analysis, which may not be going to be associated with the newer agents approved in the future. The DSAs must specify the target age group and gender of the patients in whom the advised ADRs need to be monitored. A separate alert mechanism should be put in place in case of teratogenic effects such as neural tube defects are implicated with the drugs.
Genetic predisposition toward ADRs is an emerging issue, not only in anticancer, antiviral, or antimalarial chemotherapies, but also in many other fields of medicine. Integrating pharmacogenetic data can be a potential aspect of future PV. Further, the NCC-PvPI should thrive to make available the DSAs in all the regional languages for a better understanding of the ADRs by the patients to closely monitor themselves when consuming the implicated drug. This will increase the participation of nonhealth professionals in the PV system in India.
Patient safety is paramount during disease management using medicines and therefore strong cooperation and contribution from health-care professionals and pharmaceutical companies are required to strengthen the PV system in India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]