Pharmacovigilance in Pakistan: A Peek into the Future Prospects

The dire need for drug monitoring and surveillance principles are practices governing the safety profiles of the medicines arose following the 1960’s Thalidomide disaster that resulted in phocomelia in thousands of new born babies [1]. Since then Pharmacovigilance centers have been established in the member countries, which report all the untoward drug reactions to Uppsala Monitoring Centre (UMC) that is designated to perform further investigations and global dissemination of the necessary information [2]. Currently 134 countries that are collaborating with UMC of which 96% are developed while 27% are developing countries which are lagging behind as per the unavailability of infrastructure and resources [3]. Pakistan National Pharmacovigilance Centre (PNPC) Ministry of health initiated pharmacovigilance activities in Pakistan in 1994; however a stable system could not be established owing to the unavailability of human resources as well as the infrastructure [4]. Later the suggestion for the establishment of Pakistan National Pharmacovigilance center (PNPC) was mentioned by the national drug policy in 2003 [5], however, the launch of the centre took place in 2012 following the tragic death of around 200 cardiac patients in Lahore as a result of an accidental mixing of Isosorbide mononitrate with Pyrimethamine that resulted in severe deficiency of folic acid, destroying the platelets and causing profuse internal bleeding [6,7]. In the view of the gravity of the situation, an independent authority for drug regulation (Drug regulatory authority of Pakistan – DRAP) was founded under the orders of the Pakistan Supreme Court in 2018. This authority was established for ensuring availability and safety of the medications. In order to devise an infrastructure for the post-marketing drug surveillance, DRAP in collaboration with the Pharmacopoeia of US established PNPC in the year 2017 and by 2018 Pakistan was included as a member in the UMC [8]. The centre has laid down protocols and practices for the international and national coordination and has added Pakistan 134th on the drug monitoring WHO program. Currently the PNPC is being governed by the 2012 Act of DRAP for developing, promoting and regulating the pharmacovigilance system in the country and coordination with provincial sectors to empower the hospitals to establish their own pharmacovigilance centers [9]. Future Perspectives of PNPC PNPC has come a long way still being in infancy and is setting up future goals towards development. Proper guidelines have been formed and an organized system was established by PNPC till 2018 for reporting Adverse Drug Reactions (ADRs) online. Training workshops for the members are regularly carried out to keep the work force ready and updated about the regulatory and management aspects. A regional centre of PNPC was announced to be established in Islamabad in November, 2019 [10]. PNPC has also upgraded its recording, monitoring and reporting system for ADRs via affiliation with the VigiFlow database of the country permitting maximum control locally effectively managing and analyzing the country-wide data [11]. The provincial, market authority and public health stakeholders are called for regular meetings. PNPC has composed comprehensive guidelines and legislation regarding pharmacovigilance protocols that are meant to provide legal surveillance of the activities. In the long run, the PNPC is planning for the establishment of provincial pharmacovigilance centers in each province, and the sub-regional centers and integrating them into the national database. Good practices of pharmacovigilance will utilize the obtained data to bring about safety protocols. However, a number of hurdles are still in the way. There are constraints related to logistics and legal matters as well as finances. There is a requirement of a collaborated effort by all the stake holders in the country. Healthcare professionals have a limited awareness about PNPC protocols and a reluctance to report the adverse events. The main issue is getting the healthcare workers and public normalized and used to with the reporting and surveillance system in order to cope up with the reluctance to report and awareness about the protocols. The success of this system is actually two way and it depends on the response from the reporting stake holders as much as it does on the system of the organization itself. The public health programs, hospitals and healthcare units need to be encouraged to participate in the PNPC system for proper reporting and detection of serious ADRs. Training and awareness sessions need to be conducted to form and normalize a reporting culture among heath care workers in Pakistan. Methods for assessment of severity, detection of cause and preventability of the reported ADRs, need further standardization. Furthermore, the international collaboration is still deficient as the WHO data bank does not have any adverse effect reported data from Pakistan; therefore, the gap needs to be filled as a priority. Although a lot still needs to be don e, a clear progress has been noted in the past couple of years. With the introduction of new guidelines and strategies; route to further progress is clearly marked but the effort has to involve all the stake holders which will start by the realization and understanding of the significance and need for a properly functional pharmacovigilance system in the country.

A 10-Year Single-Center Experience of Adverse Drug Reaction Monitoring

Background/Aims: Despite proper use of pharmaceuticals, adverse drug reactions (ADRs) can lead to problems related to patient safety. We analyzed the characteristics of ADRs, particularly serious adverse events (SAEs), in a single tertiary medical institution. Methods: Spontaneous ADR report data collected from 2010 to 2019 in Seoul National University Hospital were assessed. Causality was evaluated according to the World Health Organization-Uppsala Monitoring Centre criteria. Age, sex, onset, severity, seriousness, and system organ class (SOC) of ADRs and SAEs were analyzed. Results: During the study period, a total of 49,955 individual case safety reports were assessed as possible, probable, or certain. Although the number of gastrointestinal ADR reports was high (25.9%), severe cases were uncommon (2.6%). By contrast, the number of hematologic disorders was low (6.6%) but 39.2% of them were severe. Among ADRs, 10.2% were assessed as SAEs, the proportion of which was high at extreme ages and in males. Body as a whole-general disorders were the most frequently reported SOC for SAEs, followed by skin and appendage disorders. Antineoplastic agents and antibiotics were the most common causative agents of SAEs and ADRs. Anaphylactic reaction was the most frequent SAE (6.5%). Conclusions: The proportion of SAE differs according to SOC and drug. Attention should be paid to SAEs in children and older adults because the rate of SAEs is significantly higher at extreme ages.

Assessment of adverse drug reactions of psychopharmacological drugs in patients of psychiatric disorders

Introduction: Psychopharmacological drugs are used in the treatment of different types of psychotropic disorders. These drugs are associated with a variety of adverse drug reactions (ADRs). The ADRs due to psychopharmacological drugs are a significant cause of mortality and morbidity. Objectives: The current study assessed the adverse drug reactions of psychopharmacological drugs in patients with psychiatric disorders. Methods: This study was a retrospective study. All ADR forms related to psychopharmacological drugs that were reported to the pharmacovigilance center, UCMS, and GTB Hospital, between December 2019 to February 2020, were assessed to identify the incidence and nature of important ADRs. Causality assessment was done by WHO Uppsala Monitoring Centre Global Introspection Method. A total of 150 ADR forms were analyzed. Results: Females (60.66 %) experienced more ADRs than males (39.33 %). ADRs were most commonly reported in the age group of 18-28 years followed by 29-39 years. Depression was the most common diagnosis in patients with psychiatric disorders. Dizziness was the most common ADR followed by headache and insomnia. Escitalopram (12.21 %) was the most commonly implicated drug causing ADRs followed by clonazepam (9.92 %). As per the WHO causality assessment method, 77 % of ADRs were possible and 23 % were probable. Conclusions: Therefore, early detection and awareness of ADRs are important to enable health professionals to perform alterations in the prescribed drug treatment to prevent or reduce the adverse effects due to psychotropic drugs. This will improve patient care and safety as well as promote rational use of drugs.

A Diabetic Patient Complicated With Pancreatic Cancer After Using Liraglutide: A Case Report

BackgroundDiabetes and cancer are both multifactorial diseases, and epidemiologic evidence indicates that diabetes may be associated with the incidence of certain types of cancer. In diabetes the risk of pancreatic cancer is increased significantly. However, whether certain diabetes treatment being related with the risk of pancreatic cancer remains unclear. In this report, we presented a case of pancreatic ductal adenocarcinoma in a diabetic patient in China after being treated with liraglutide, a novel glucagon-like peptide-1 (GLP-1) analog.Case reportA 71-year-old Han Chinese man who had had a type 2 diabetes for 25 years presented at the endocrinology department with discomfort in the left upper quadrant of abdomen for 10 days. The patient’s vital signs and laboratory findings were unremarkable except for the elevated level of carbohydrate antigen (CA19-9). The upper abdomen routine enhanced computed tomography (CT) scan showed low density of the pancreatic body and tail, and the histopathological result of the pancreatic biopsy samples was pancreatic ductal adenocarcinoma with regional lymph node metastasis. We reviewed his former medical records and found that liraglutide was added to his hypoglycemic treatment regimen 20 months ago. At that time, the level of tumor biomarkers and upper abdomen routine CT were unremarkable. We estimated the causality between liraglutide and pancreatic cancer by the Naranjo Adverse Drug Reaction Probability scale and WHO-Uppsala Monitoring Centre (WHO-UMC) system, and the causality turned out to be possible.ConclusionOur report suggests that liraglutide may be related with the genesis and development of pancreatic cancer and also highlights the importance of regular checkups in diabetic patients treated with liraglutide. However, our report has some notable limitations, and further longer-term follow-up trials with larger sample should be conducted in future to assess the causality between liraglutide and pancreatic cancer.

A STUDY OF AGREEMENT BETWEEN WHO-UPPSALA MONITORING CENTRE CRITERIA, NARANJO ALGORITHM, AND LIVERPOOL ALGORITHM FOR CAUSALITY ASSESSMENT OF ADVERSE DRUG REACTIONS

Objective: A standard causality assessment tool of an adverse drug reaction (ADR) is essential to compute the risk-benefit assessment of the medication taken by the patient and categorize its relationship likelihood. It should be reproducible and should not differ with the background and experience of the evaluator. Though there are a large number of causality assessment tools, none is unanimously accepted worldwide. So, this study was done to assess the agreement between three frequently used methods of causality assessment, the World Health Organisation-Uppsala Monitoring Centre (WHO-UMC) system, the Naranjo’s algorithm, and the Liverpool algorithm. Methods: 172 ADR forms from the pharmacovigilance unit were randomly selected for the study. Causality assessment was done using three different methods, the WHO-UMC system, Naranjo’s algorithm, and the Liver pool algorithm. Cohen’s Kappa statistics was applied to look for agreement between the causality assessment methods. Results: The agreement between the WHO-UMC criteria and Naranjo’s algorithm was the highest (136), with a Kappa value of 0.511, suggesting a moderate level of agreement. A maximum number of disagreements were noted between the WHO-UMC system and the Liverpool algorithm method (110). Conclusion: A moderate agreement exists between the WHO-UMC system and the Naranjo algorithm. There is poor agreement between the Liverpool algorithm and the other two scales. Therefore, it is recommended that both the WHO-UMC system and the Naranjo algorithm be used for causality assessment of ADRs.

LEVETIRACETAM INDUCED URTICARIA IN PATIENT OF FOCAL SEIZURES; A CASE REPORT

Drug rash due to medications are common and can be serious leading to increase in morbidity and mortality. Drug rash can be caused by antiepileptic medications also. We are reporting a case of cutaneous reaction secondary to levetiracetam. A 22 years old female presented to the hospital with history of three episodes of seizures. She was diagnosed with focal seizures with secondary generalization and was prescribed tablet levetiracetam 500 mg twice a day for seizure prophylaxis. After 3rd dose, the patient developed diffuse, erythematous and itchy rashes over whole body without any breathing difculties. Levetiracetam was discontinued, and tablet lacosamide 200 mg twice daily was substituted. After 1 day, the rash dissipated. Our case was classied as drug-induced urticaria with red itchy hives. The world health organization Uppsala monitoring Centre (WHO-UMC) causality assessment system suggested a probable/likely cause for levetiracetam-induced skin reaction. Levetiracetam seemingly have fewer side effects than the traditional antiepileptic medications but it is important for the healthcare providers to continuously monitor the medication for adverse effects, so that necessary modications and required labeling may be reformed in-time.

Quantifying and Categorizing ADRs in Psychiatric Residential Long-Stay Patients Utilizing UKU-SERS Scale

Background: Psychotropic drugs are essential but not devoid of adverse drug reactions (ADRs), which lead to non-compliance and further failure of therapy, hampering the patient’s quality of life. Methods: A cross-sectional, observational study was carried out in a residential nursing home in Pune, India, from October 2018 to March 2019. Psychiatric inpatients of both genders and all ages receiving psychotropic drugs for at least one month were enrolled. Patients who were not alert or oriented enough to give a detailed history and response to a questionnaire, including dementia patients, and those who were not willing to give informed consent were excluded. The ADRs were categorized, and their management was documented using the Udvalg for Kliniske Unders gelser (UKU) side effect rating scale. ADRs were assessed for causality and severity using the WHO-Uppsala Monitoring Centre (WHO-UMC) causality assessment scale and the Modified Hartwig and Siegel scale. Results: In our study, 115 patients (76.6%) experienced 273 adverse drug events. Atypical antipsychotics accounted for the maximum number of ADRs (54.94%; n = 150). The most common ADRs were weight gain, constipation, and tremors. The majority of ADRs were “mild” and had a “possible” causality relationship. Conclusion: The study demonstrated a high incidence of ADRs, which was primarily managed either by reduction of dose or continued drug use with the treatment of side effects.

Signals of adverse drug reactions communicated by pharmacovigilance stakeholders: protocol for a scoping review of the global literature

Background: Signals of adverse drug reactions (ADRs) form the basis of some regulatory risk-minimization actions in pharmacovigilance. Reviews of limited scope have highlighted that such signals are mostly supported by reports of ADRs or multiple types of evidence. . The time that elapses between a report of a suspected ADR and the communication of a signal has not been systematically characterized. Neither have the features of reports of suspected ADRs that authors used to support putative causal relationships, although difficulties with establishing causal relationships between medicinal products and adverse events have been highlighted. The objectives of this study will be to describe the evidence underpinning signals in pharmacovigilance, the features of reports of ADRs supporting signals, and the time that it takes to communicate a signal.Methods: . We shall retrieve records from PubMed, EMBASE, Web of Science, PsycINFO (from inception onwards), without language/design restrictions and apply backward citation screening . We shall hand-search the websites of 35 regulatory agencies/authorities, restricted publications from the Uppsala Monitoring Centre, and drug bulletins. Signals will be requested from the competent stakeholder, if absent from websites. We shall use VigiBase, the World Health Organization’s Global Individual Case Safety Report database, to determine the dates on which ADRs were reported . We shall manage records using EndNote (v. 8.2); one reviewer will screen titles/abstracts and full texts, a second will cross-validate the findings, and a third will arbitrate disagreements. Data will be charted via the Systematic Reviews Data Repository, following the same procedures as for data retrieval. Evidence will be categorized according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Features of reports of ADRs will be coded. Tables will display frequencies of types of evidence and features of reports of ADRs. We shall use plots or pictograms (if appropriate) to represent the time from the first report of a suspected ADR to a signal.Discussion: We expect the findings from this review will allow better understanding of global patterns of similarities or differences in terms of supporting evidence and timing of communications, and identify relevant research questions for future systematic reviews.Scoping review registration: osf.io/jtv38

Enoxaparin induced reactive thrombocytosis: a rare adverse drug reaction

ObjectivesEnoxaparin is a low molecular weight heparin (LMWH), which belongs to the class of anticoagulants. The drug is administered as subcutaneous injection to prevent or treat deep vein thrombosis (DVT), pulmonary embolism and ischemic complications.Case PresentationA 57-year-old women diagnosed with acute coronary syndrome developed reactive thrombocytosis following the administration of enoxaparin subcutaneously. The blood test reports of the patient showed that there is a gradual elevation of platelet count day by day following enoxaparin administration. On an assessment using both World Health Organization–Uppsala Monitoring Centre (WHO–UMC) scale and Naranjo Causality Assessment Scale indicated that enoxaparin is the “probable” cause for the reaction.ConclusionsWe conclude that reactive thrombocytosis is a probable adverse drug reaction and close monitoring of blood counts is essential, following enoxaparin injection. More studies are to be conducted to identify further complications.