WHO Causality Assessment Research Articles

Adverse Drug Reactions Due to Cancer Chemotherapy in Females = تحليل حدوث التفاعلات الدوائية الضارة في المرضى الذين يتلقون العلاج الكيميائي من السرطان من الإناث

Chemotherapy | Adverse Drug Reactions | Cancer | Hartwig and Siegel Scale | WHO Causality Assessment Scale | Naranjo's Algorithm | العلاج الكيميائي | التفاعلات الدوائية الضارة | السرطان | مقياس هارتفيغ و سيجل المعدل | مقياس تقييم منظمة الصحة العالمية السببية | خوارزمية نارانخول

Anticancer drug induced palmar plantar erythrodysesthesia.

Palmar plantar erythrodysesthesia (PPE) is a dose limiting toxicity of anticancer agents. In some cases it may mandate for discontinuation of anticancer agents. Evaluation of data of PPE among reported adverse drug reactions (ADRs) from the Department of Medical Oncology could quantify the burden. To evaluate and analyse the PPE among reported ADRs from medical Oncology. The data of all cases of reported PPE were collected during January 2012 to September 2013 and were analysed with WHO causality assessment scale. The severity was clinically graded. The follow-up data regarding outcome of ADRs were also noted. During the study period of 21 months a total of 1418 ADRs have been reported from 1076 patients. Among them PPE was reported from 31 cases (2.9%). Majority (32.2%) of these patients were on chemotherapy for breast cancer. Patient's age ranged from 17 to 68 y and the median age was 50 y. There were 18 female (58%) and 13 male patients (42%). Capecitabine was the leading drug involved in PPE, reported with 20 cases (64.5%), and followed by docetaxel with 5 cases (16.1%). Majority (67.7%) of the reactions was categorized as certain and 64.5% was grade II severity clinically. Our findings show that PPE accounts for 2.9% of total reported ADRs from Medical Oncology during 21 months. Majority of the reactions were classified as certain. Capecitabine is commonly implicated drug.

Safety and Tolerability Profile of Artemisinin-Based Antimalarial Combination Therapy in Adult Patients in Benin City, Nigeria

The WHO in 2001 advocated artemisinin- based antimalarial combination therapy (ACT), which was adopted by Nigeria in 2005. The objective of this study was to characterize the safety and tolerability profile of the ACTs in adult patients with uncomplicated malaria. A descriptive longitudinal study was conducted in the General Practice Clinic–of the University of Benin Teaching Hospital (UBTH) and the Central Hospital, Benin City, South-South Nigeria, between October 2009 and March 2010. Adult patients (e”18years) with a diagnosis of uncomplicated malaria and treated with ACTs were recruited for the study. The safety and tolerability profile of ACTs amongst the treated patients were assessed after 9 days of follow up via telephone calls. Adverse Events were classified using the WHO causalityassessment. Five hundred patients were enrolled for this study – Artemether/Lumefantrine (AL) (179), Artesunate/Mefloquine (AM) (149), Artesunate/Amodiauine (AA) (134) Artesunate/Sulphadoxine/Pyrimethamine (ASP) (22), Dihydroartemisinin/ Piperaquine (DP) (16). The mean age of the respondents was 32.6years (range 18-68yrs). One hundred and eighty-eight (37.6%) of the total number of patients followed up reported at least one Adverse Events: 61% in the AA, 60% in the AM, 58% in the AL, 31% in DP, 4 of 19 (21.1%) in ASP. AA treatment was associated with a significant higher risk of gastrointestinal symptoms, dizziness and pruritus than AL and AM (p<0.05). Those treated with AM had a higher incidence of generalized weakness. Ten of the respondents discontinued therapy due to Adverse events experienced: AM (4), AA (4), AL (1), DP (1). Severe AEs were observed in two of these pateints that were given AA and AM respectively. The safety and tolerability of artemetherlumefantrine (AL) and dihydroartemisinin piperaquine (DP) was confirmed in this study. The other recommended ACTs (artesunate-amodiaquine (AA) and artesunate mefloquine (AM) although safe, were less well tolerated and this may affect patients’ adherence with its attendant consequences. Keywords: Artemisinin-based Combination therapy, Adverse Events, Malaria

Pharmacovigilance study of adverse cutaneous drug reactions in a tertiary care hospital

Background: The wide and indiscriminate use of drugs has increased the incidence and the modes of presentation of cutaneous drug reaction. Adverse cutaneous drug reactions are common, comprehensive information about their incidence, severity and ultimate health effects are unavailable. Objective: To study and evaluate incidence of adverse cutaneous drug reaction (ACDR) at our tertiary care hospital and assess the impact of active surveillance on adverse drug reaction (ADR) reporting. Materials and Methods: Prospective study involving 29,156 patients was carried out by active observation of patients attending Dermatology department over a period of 21 months. Retrospective study involving 61000 patients attended Dermatology OPD over last 4 years was carried by available data of dermatology department. Both the studies were compared by chi square test. Results: In prospective study 48 (0.17%) were diagnosed as having ACDR. Acneform eruption (25%) followed by fixed drug eruption (FDE) (22.92%) were the most common morphological forms. The most common drugs responsible were betamethasone, isoniazid and rifampicin for acneform eruption, while metronidazole and paracetamol for FDE. WHO causality assessment showed 13 were certain, 24 were probable and 11 were possible in nature. Hartwig severity assessment revealed 40 were moderate, 07 were mild and 01 was severe. Modified Schomock and Thronton scale showed 37.5% were definitely preventable, 33.33% were probably preventable and 29.17% were not preventable. In retrospective study 63 (0.10%) ACDRs were reported, out of them FDE was most common (28.57%), followed by acneform eruption (11.11%). Antimalarials and metronidazole were most commonly responsible for FDE while systemic steroids were responsible for acneform eruption. There is significant association between both the studies with higher incidence in prospective study (p

Characteristics and Clinical Implications of the Pharmacokinetic Profile of Ibuprofen in Patients with Knee Osteoarthritis

Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800mg/day to 1800mg/day) administered in patients affected by severe knee OA. Ibuprofen was administered for 7days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

Autoimmune disorders after immunisation with Influenza A/H1N1 vaccines with and without adjuvant: EudraVigilance data and literature review

All suspected autoimmune disorders (AID) reported as adverse reactions to EudraVigilance from 1 October 2009 to 31 December 2010 for adjuvanted (Celtura™, Fluval P™, Focetria™ and Pandemrix™) and non-adjuvanted (Cantgrip™, Celvapan™ and Panenza™) pandemic Influenza A/H1N1 vaccines were analysed to determine whether adjuvanted vaccines were associated with higher reporting of AID than non-adjuvanted ones. AID were identified based on the corresponding MedDRA High Level Group Term. Reports of type 1 diabetes mellitus and multiple sclerosis were also included in the analysis. Causality was assessed based on WHO causality assessment for adverse events following immunisation and Brighton Collaboration criteria for Guillain-Barré syndrome (GBS), idiopathic thrombocytopenic purpura and acute disseminated encephalomyelitis. Of the 50,221 adverse reactions received in EudraVigilance for A/H1N1 vaccines (adjuvanted: 46,173, non-adjuvanted: 4048), 314 were AID (adjuvanted: 276, non-adjuvanted: 38). GBS was the AID with the highest number of reports (125, adjuvanted: 109, non-adjuvanted: 16). Reporting ratios as calculated by the percentages of AID amongst all reported adverse reactions were 0.60% (95% CI: 0.53–0.67) and 0.94% (95% CI: 0.64–1.24) for adjuvanted and non-adjuvanted vaccines, and were 0.26% (95% CI: 0.22–0.31) and 0.37% (95% CI: 0.18–0.56) in a restricted analysis based on diagnostic certainty, causal relationship and plausible temporal association. Reporting rates for all reports of AID using the estimated number of vaccinees as denominator were 6.87 (95% CI: 6.06–7.68) and 9.98 (95% CI: 6.81–13.16) per million for adjuvanted and non-adjuvanted vaccines, and 3.01 (95% CI: 2.47–3.55) and 3.94 (95% CI: 1.95–5.94) per million in the restricted analysis. These results do not suggest a difference in the reporting of AID between adjuvanted and non-adjuvanted A/H1N1 vaccines. In a literature review performed on 31 August 2011, GBS was also the AID the most frequently discussed in association with A/H1N1 vaccination; reporting rates were generally within expected background rates.

Mortality in Children and Adolescents Prescribed Antipsychotic Medication

Antipsychotic prescribing in children has risen in many countries; however, the safety of these agents in the young has not yet been fully established. Potentially fatal antipsychotic-related adverse events include cardiac complications and neuroleptic malignant syndrome. The objective of this study was to investigate mortality in children and adolescents taking antipsychotic medication. The General Practice Research Database (GPRD) was used as a data source for this study. Cases were identified from a cohort of patients previously studied. The study population encompassed all patients aged 18 years and under who received at least one prescription for an antipsychotic from 1 January 1992 to 31 December 2005. Patients were followed from the date of the first antipsychotic drug prescription until the earliest occurrence of a code of death, age >18 years or the end of the study period. Cases of death were identified by screening patients' medical records for clinical or referral events with events indicating death, or if a transferred-out patient has a 'transfer out reason' specified as 'death'. Confirmation of cases was carried out by examining individual patient profiles and from questionnaires sent to GPs. If necessary, the death certificates and/or post mortem reports were obtained by the source data verification service the GPRD provide. Once cases of death were identified, crude mortality rate (CMR) and standardized mortality ratio (SMR) were calculated. Baseline mortality rates were obtained from the Office for National Statistics. A modified WHO causality assessment was conducted to determine the likelihood of a relationship between the drug and an event of death. The cohort contained 2767 patients who received at least one antipsychotic prescription. There were 30 deceased cases in the cohort. The GP questionnaire response rate was 97%. Of the 30 cases, 24 were related to pre-existing medical conditions, including neoplastic diseases and HIV. After excluding these patients, six cases of death from 5963 person-years and 1958 treatment-years remained. The median age of death was 17 years (interquartile range 14-17.75). The overall CMR was 1.01 per 1000 person-years at risk (95% CI 0.20, 1.81) and SMR was 4.03 (95% CI 1.48, 8.76). Of the six cases, only one was deemed possibly associated with antipsychotic therapy, based on the causality assessment analysis conducted; CMR based on this case was 0.51 per 1000 treatment-years (95% CI 0.09, 2.89). The remaining five cases of death were unlikely to be associated with antipsychotic therapy. Our study demonstrated an elevated SMR in patients exposed to antipsychotics. However, the elevated SMR was unlikely caused by antipsychotic treatment, but would suggest the possibility of inadequate management or poor control of patients' underlying medical conditions prior to death.

The pharmacovigilance-center FAKOS – Detection of drug induced agranulocytosis, immune thrombocytopenia, hepatitis, pancreatitis, LongQT-Syndrome and Torsade de pointes

Background and Aim: Adverse drug reactions (ADR) are an important cause of morbidity and mortality. The Berlin Pharmacovigilance Center PVZ-FAKOS uses an active surveillance approach to identify hospitalised patients with serious rare, however often drug-induced diseases. Aim of FAKOS is to assess potential drug risks for the following diseases: acute Agranulocytosis (AGR), Immune Thrombocytopenia (ITP), acute Hepatitis (HEP), acute Pancreatitis (PAN), and LongQT Syndrome/Torsade de pointes (LQT/TdP). Materials and Methods: FAKOS recruits patients (age ≥18) with AGR and ITP (2000–2009), HEP and PAN (2002–2009) and LQT/TdP (2008–2009) from all Berlin hospitals. Only patients with idiosyncratic or drug-induced disease of the different disease entities are included. Information on drugs and other exposures is ascertained in a standardized personal interview. For each patient, a drug causality assessment is conducted according to the WHO causality assessment criteria. Results: Whereas most patients with AGR and HEP (&gt;90%) were categorized as possibly drug associated, for 65% of PAN and LQT/TdP and for 40% of ITP. The number of different drugs classified as at least probably causing one of the diseases were N=48 for AGR, N=57 for HEP, N=14 for PAN, N=19 for LQT/TdP and N=26 for ITP. Of those, suspected drugs assessed in &gt;2 cases were for AGR: Metamizole N=10, Clozapine N=10, Methimazole N=6, Sulfasalazine N=5; for HEP: Phenprocoumon N=5, Flupirtine N=5, Simvastatine, Clarithromycine, Ciprofloxacine, Moxifloxacine, Diclofenac and Olanzapine each with N=3; for PAN: Azathioprine N=4, for ITP: Tirofibane N=8; for LQT/TdP: (Levo-)/Methadon N=5. Conclusion: A broad range of drugs has to be considered in patients with unknown etiology of AGR, ITP, HEP, PAN and LQT/TdP. The disease based, active surveillance approach of PVZ-FAKOS with standardized causality assessment potentially overcomes problems of underdetection and underreporting of ADR. Acknowledgement: PVZ-FAKOS is being funded by the Federal Institute for Drugs and Medical Devices, Germany.

A prospective analysis of drug-induced acute cutaneous reactions reported in patients at a tertiary care hospital

Sir, An adverse cutaneous drug reaction (ACDR) is an undesirable change in structure and function of the skin, its appendages, or mucous membranes due to drugs.[1] ACDRs are the most common among the various reactions attributed by the drugs.[2] Drug eruptions vary in their appearance, rapidity of onset, severity, and underlying immunopathological mechanisms. They can range from pruritus or rash to severe and life-threatening Stevens Johnson Syndrome or toxic epidermal necrolysis. The cutaneous eruptions are visible to the patient and hence their reporting is better and early as compared to the drug reactions involving internal organs and systems. Similarly, the response to the treatment for the cutaneous drug reactions is also better perceived. Many of the commonly used drugs can produce ACDRs. Some severe cutaneous ADRs may result in serious morbidity and even death.[3] In this study, cases of adverse cutaneous drug reactions (ACDRs) were analyzed from both the outpatient and inpatient departments of dermatology at SSG Hospital, Vadodara, Gujarat, to categorize and analyze the reported ACDRs, to evaluate the management and outcome and to assess the causality of the reported ACDRs, and to educate the patients for prevention of their recurrence. Total 70 cases, which had certain, probable or possible relation according to WHO causality assessment criteria, were included in the study. All ACDRs were assessed and analyzed for number of incidences, drug class, individual drug causing ACDRs, and type of cutaneous reactions. Diagnosis and treatment of ACDRs were done by dermatologists of the hospital. We had excluded cases of cutaneous reactions where drugs taken were not known due to patient's unawareness or unavailability of records/prescription. ADR alert cards were given to the patients and they were asked to produce the same while visiting the physician in future. Most of the patients of ACDRs were in the age group of 11-50 years. Male patients had predominance over female patients. In this study, most cases had reaction time between 1 to 7 days. The most common morphological types of ACDRs were fixed drug eruptions (37.1%) [Figure 1] and maculopapular rash (28.6%). Stevens-Johnson syndrome, dapsone syndrome [Figure 2], and exfoliative dermatitis were the serious ACDRs. Antimicrobials (61.4%), nonsteroidal anti-inflammatory drugs (NSAIDs) (22.9%), and antiepileptic drugs (10%) were the most prominent group of drug responsible for ACDRs. Figure 1 A case of bullous-fixed drug eruption by cotrimoxazole Figure 2 A case of Dapsone syndrome Pudukadan,[4] Chatterjee et al.,[5] and Sharma[6] reported antimicrobials as a major group producing ACDRs followed by antiepileptics and NSAIDs. This indicates regional differences in occurrence of ACDRs probably due to the difference in prescribing patterns of drugs. Maximum number of cases i.e. 15 (21.4%) were due to cotrimoxazole. Among NSAIDs, maximum number (10%) of cases were due to ibuprofen followed by diclofenac (4.3%). Among antiepileptics, phenytoin was implicated in 5 (7.1%) and carbamazepine in 2 (2.9%) cases. ACDRs to some new drugs were also observed like nevirapine-induced maculopapular rash, isotretinoin-induced oral cheilitis, and vitamin B complex-induced maculopapular rash. Out of 70 patients, 68 (97.2%) were cured either due to withdrawal of offending drug or due to appropriate drug therapy to the patients. Among the two cases, one patient developed hyperpigmentation after dechallenge, while the other patient did not return to follow-up after dechallenge. A causal relationship between the drug and the reaction was assessed by using WHO-UMC classification for causality assessment depending upon the lag period between the start of the drug and appearance of the reaction (reaction time), response to dechallenge, and the available data about the drug. According to the WHO-UMC criteria, 9 (12.9%) cases were certain, 59 (84.2%) cases were probable, and 2 (2.9%) of reported ACDRs were possible due to drugs. Since most of the patients attending this hospital belong to relatively poor socio-economic status, the pattern of drug usage amongst them is mostly restricted to drugs that are supplied free of cost from the hospital. This was an important limitation of this study as the suspected drug information generated from this study may not be truly reflective of the pattern in other health care centers catering to patients of higher socio-economic status. The observations made in our study emphasize the need for a strict and efficient pharmacovigilance system which could curtail the incidence ACDRs in clinical practice.

Statin-Associated Psychiatric Adverse Events

The inhibitors of HMG-CoA reductase ('statins') are widely prescribed hypolipidaemic drugs, which have been evaluated in several clinical trials involving hundreds of thousands of patients. From a safety perspective, both clinical trials and post-marketing surveillance have demonstrated that statins are generally well tolerated, with rare serious adverse drug reactions (ADRs) that affect mainly muscle, liver and kidney. However, recent interest has been focused on a potential risk of psychiatric ADRs associated with statins, including memory loss, depression, suicidality, aggression and antisocial behaviour. Special attention is currently being paid to the potential for statin-induced sleep disorders. To investigate the hypothesis that statins may be associated with psychiatric adverse events using quantitative and qualitative signal analysis. The Interregional Group of Pharmacovigilance database holds reports of suspected ADRs submitted since 1988 from eight Italian regions. In the present analysis, only reports ranked at least 'possible', according to WHO causality assessment criteria, were considered. Association between statins and psychiatric events was assessed by the case/non-case methodology, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Cases were defined as patients with at least one reported ADR combined with the system organ class (SOC) 'psychiatric disorders'. The non-cases comprised all patients who did not experience an ADR related to the SOC 'psychiatric disorders'. Index reports comprised all ADR reports involving at least one statin, while all ADR reports not involving statins as suspected drugs were used as controls. According to selection criteria, 35,314 reports were included in the analysis. A total of 71 psychiatric preferred terms combined with statins were identified in 60 reports. Among them, 14 reports (23.3%) noted a positive rechallenge. Both the unadjusted (0.8; 95% CI 0.6, 1.1) and adjusted ROR (0.7; 95% CI 0.6, 1.0) suggested a lower rate of reports of psychiatric events for statins as a whole class compared with all other drugs, although the difference was not significant. The five most frequently reported psychiatric events combined with statins were insomnia, somnolence, agitation, confusion and hallucination. Only insomnia was reported with higher frequency for statins compared with all other drugs (ROR = 3.3; 95% CI 1.9, 5.7), while confusion was reported with a lower frequency (ROR = 0.4; 95% CI 0.1, 0.9). Amongst statins available in Italy, only simvastatin (ROR = 0.5; 95% CI 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events compared with all other drugs together. A relatively small number of possible statin-associated psychiatric ADRs have been found in our database. No significant risks for a higher overall reporting of psychiatric ADRs associated with statins were identified in comparison with all other drugs combined. However, statin-associated insomnia resulted in a significant ROR that requires further investigation.

Ocular Adverse Effects Associated with Systemic Medications

This article reviews several retrospective case series and reported adverse events regarding common ocular adverse effects related to systemic therapy. It is not intended as a comprehensive summary of these well described adverse drug reactions, nor is it intended to cover the complete spectrum of all ocular adverse effects of systemic therapy. Many systemic drugs may produce ocular toxicity, including bisphosphonates, topiramate, vigabatrin, isotretinoin and other retinoids, amiodarone, ethambutol, chloroquine and hydroxychloroquine, tamoxifen, quetiapine, cyclo-oxygenase (COX)-2 inhibitors, erectile dysfunction agents and some herbal medications. For this review, the certainty of the adverse effect profile of each medication was evaluated according to the WHO Causality Assessment Guide.A certain relationship has been established for pamidronate and alendronate as causes of scleritis, uveitis, conjunctivitis and blurred vision. Topiramate has been established as adversely causing symptoms consistent with acute angle-closure glaucoma, typically bilateral. Vigabatrin has been shown to cause bilateral irreversible visual field defects attributed to underlying medication-induced retinal pathology. Isotretinoin should be considered in the differential diagnosis of any patient with pseudotumour cerebri. Patients taking amiodarone and hydroxychloroquine should be monitored and screened regularly for development of optic neuropathy and maculopathy, respectively. Sildenafil has been reported to cause several changes in visual perception and is a possible, not yet certain, cause of anterior ischaemic optic neuropathy. Patients taking tamoxifen should also be monitored for development of dose-dependent maculopathy and decreased colour vision. COX-2 inhibitors should be included in the differential diagnosis of reversible conjunctivitis. Several herbal medications including canthaxanthine, chamomile, datura, Echinacea purpurea, Ginkgo biloba and liquorice have also been associated with several ocular adverse effects. It is the role of all healthcare professionals to detect, treat and educate the public about adverse reactions to medications as they are an important health problem.