Unexpected Adverse Drug Reactions Research Articles

Genetic Polymorphisms and <i>in Vitro</i> Functional Characterization of CYP2C8, CYP2C9, and CYP2C19 Allelic Variants

Genetic variations in CYP 2C (CYP2C) subfamily, CYP2C8, CYP2C9, and CYP2C19 contribute to interindividual variability in the metabolism of clinically used drugs. Changes in the drug metabolizing activity of CYP2C members may cause unexpected and serious adverse drug reactions and inadequate therapeutic effects. Therefore, CYP2C gene polymorphism is used as a genome biomarker for predicting responsiveness to administered drugs. The most direct method for understanding the extent of the effects of CYP2C gene polymorphism on drug pharmacokinetics is by evaluating the blood and urine concentrations of the drug in subjects. However, in vivo tests are highly invasive, and considering the risk of adverse drug reactions, the burden on the patient may be significant. In addition, examining the functions of rare variant enzymes with an allele frequency of ≤1% requires at least several hundred subjects. Furthermore, it is extremely difficult to evaluate the functions of all variant enzymes in an in vivo test. On the other hand, in vitro enzyme activity can be evaluated using a heterologous expression system to avoid the aforementioned problems. In vitro tests are extremely important as they complement in vivo information. This review focuses on recent findings of in vitro studies on 3 highly polymorphic CYP2C members: CYP2C8, CYP2C9, and CYP2C19.

Adverse drug reaction profile of microtubule-damaging antineoplastic drugs: A focused pharmacovigilance study in India.

Objectives:The aim of the study was to analyze the adverse drug reaction (ADR) profile of microtubule-damaging antineoplastic drugs (taxanes and vinca alkaloids) and to look for unexpected ADRs among the local population. Focused study on these drugs, rampantly used in oncology department for a wide variety of tumors including early and advanced malignancies, would enable better treatment care by physicians.Materials and Methods:Data on ADRs were collected from the cancer patients belonging to both gender and of all ages, on taxanes- or vinca-based cancer chemotherapy and reported in the Indian Pharmacopoeia Commission form. Causality was assessed using the WHO criteria and Naranjo's Algorithm. Preventability and severity of ADRs were also assessed.Results:A total of 97 ADRs were reported among 488 patients on microtubule-damaging anticancer drugs admitted over a period of 1 year. The incidence rate was 19.87%. Gastrointestinal system (40.2%) was the most affected followed by bone marrow (33%) and skin (8.2%). The highest incidence of ADRs was reported among paclitaxel (54.6%), and vincristine (39.2%). Most of the reported ADRs were of milder nature and preventable. The WHO causality assessment scale indicated 71.1% possible reactions.Conclusions:This study showed that most ADRs are preventable with effective ADR monitoring. There is a great need to create awareness among healthcare professionals regarding the importance of the pharmacovigilance system. Judicious use of the preventive measures will lead to a reduction in the incidence of ADRs due to the drug armamentarium, thereby enabling additional economic benefit to the patient and society.

Safety and Efficacy of Zonisamide in Patients with Epilepsy: A Post-Marketing Surveillance Study.

Background and Purpose:Zonisamide (ZNS) is one of new antiepileptic drug, which is known to inhibit seizure through multiple mechanisms of action. In Korea, ZNS was approved as an antiepileptic drug in 1992 and has been used for epilepsy patients with partial and generalized seizures. The objective of this study was to investigate the efficacy and tolerability of ZNS in patients with epilepsy and to identify the incidence of adverse events in real clinical setting.Methods:This study was carried out in patients who received ZNS for epilepsy. Patients who were observed for at least 12 weeks after treatment with ZNS were included as evaluable subjects. Information regarding the status and type of adverse events occurring during the course of treatment with ZNS was obtained regardless of causal relationship to ZNS and efficacy was assessed by the study physicians and patients at 12 weeks post dose of ZNS.Results:A total of 1,948 patients were included in the study, and ZNS efficacy was evaluated in 1,744 patients. ZNS was used as a monotherapy in 1,095 patients and as an adjunctive drug in 853 patients. Of the total patients, 1,345 (69.1%) patients had partial seizure, 563 patients had generalized seizure, and 40 patients were undetermined. Adverse events were reported in 65 patients (3.34%) including 1 case of Stevens-Johnson syndrome, but no incidence of serious unexpected adverse drug reactions were reported. 755 patients (43.29%) became seizure free with ZNS treatment, and additional 322 patients (18.41%) experienced marked improvement with ZNS treatment.Conclusions:Our study shows the safety and tolerability of ZNS treatment in patients with epilepsy in real clinical setting. In addition, ZNS was found to be an effective option as a monotherapy or in patients with generalized seizure.

Consumer Narratives in ADR Reporting: An Important Aspect of Public Health? Experiences from Reports to a Swedish Consumer Organization.

Harms of drugs are an important cause of mortality and morbidity. The use of pharmaceuticals always entails a risk of adverse events, often to an unknown extent, and increased drug utilization has made drug-related problems a common occurrence (1). It is, for instance, estimated that adverse drug reactions (ADRs) cause the European Union almost 200,000 deaths annually (2) and cost approximately €79 billion (3). The World Health Organization (WHO) clearly recognizes the need for prescribed medicines to be of good quality, safe, effective, and used by the right patient in the right dose at the right time in order to minimize the risk of harm (4). The thalidomide disaster around 1960 underscored the necessity of systems to monitor medicines safety after marketing. As a consequence, governments developed systems in order to affirm that drug products are safe and efficacious enough to be permitted on the market and that the pharmaceutical industry needed to be regulated since these companies have a responsibility to protect public health (5). This concern with patient safety and the rational usage of drugs is often referred to as pharmacovigilance (PV) (6), which can be defined as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse events or any other possible drug-related problems” (7). It is however well established that knowledge about medicines safety is limited at the time of licensing of a new product and spontaneous reporting of ADRs to regulatory authorities and drug manufactures is perhaps the most important way of monitoring the post-market safety of medicines (8). National databases to collect signals of ADRs from health care professionals (HCPs) were established already from the late 1960s and a WHO international collaboration started in 1968. With their Drug Monitoring Program, WHO supports the reporting of potential ADRs by HCPs (9), but it is a well-recognized problem by the Organization, that this group under-report serious and fatal reactions (4). Unexpected ADRs are, for instance, seldom reported.

Effectiveness, tolerability and acceptance of a low-dosed estradiol/dienogest formulation (Lafamme 1 mg/2 mg) for the treatment of menopausal complaints: a non-interventional observational study over 6 cycles of 28 days

Background: Concern and controversy characterize nowadays the use of hormone therapy for management of patients with menopausal complaints. This observational non-interventional study examined the use of a marketed oral formulation containing 1 mg estradiol valerate and 2 mg dienogest for treatment of menopausal symptoms in 1292 women visiting 243 gynecological practices in Germany.Methods: Score changes in the Menopausal Rating Scale (MRS) after three and six 28-day cycles were primary endpoints. Subjective reports on skin- and hair-related complaints and satisfaction with treatment effects were assessed. The incidence of adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding was evaluated.Results: MRS total score decreased substantially and stronger than the clinically relevant change of 5 points (p < 0.0001) as compared with baseline. Subjective skin- and hair-related complaints declined. No unexpected ADRs were reported. AEs (including ADRs) were registered in 8.8% of the participants; most frequent AEs/ADRs were postmenopausal hemorrhage (2.9%) and drug ineffective (1.4%). Nearly 76% of the subjects remained amenorrheic. Approximately 90% of the patients rated the medication’s effectiveness/tolerability as good/very good; 84% intended to continue the treatment.Conclusion: This low-dose estradiol/dienogest formulation proved efficient and well-tolerated option for the alleviation of menopausal symptoms associated with estrogen deficiency.

Effect of an educational intervention to improve adverse drug reaction reporting in physicians: a cluster randomized controlled trial.

The yellow-card scheme continues to be one of the principal methods for signal generation in pharmacovigilance. Nevertheless, under-reporting, one of its disadvantages, delays alert signals and has a negative influence on public health. Educational interventions in pharmacovigilance may have a positive impact on the spontaneous reporting of adverse drug reactions (ADRs). To assess the duration of the effect and effectiveness of an educational intervention in pharmacovigilance designed to improve ADR reporting in a robust pharmacovigilance system. A spatial, cluster randomized controlled trial was conducted covering all National Health System physicians in the northwest of Spain and targeting those who were actively engaged in clinical practice (n = 7,498). Of these, 2,120 were assigned in three spatial clusters to the intervention group (six hospitals and 138 primary care centers) and 3,614 in four clusters to the control group (seven hospitals and 267 primary care centers). The educational intervention consisted of two complementary approaches--one active (group sessions), the other passive (educational material, reporting form)-implemented from November 2007 to December 2008, with a follow-up period of 8 months. Intervention participation was 53.7 % in a hospital setting and 60.5 % in primary care settings. ADR reporting in the intervention group increased by 65.4 % (95 % confidence interval [CI]: 8.2-153.4) across the follow-up. The ADR reporting rate per 1,000 physicians/year in the intervention group rose from 28.1 to 39.6 following the intervention (51.7 and 27.4 in the first and second 4-month period, respectively). For the intervention group, relative risk (RR) was 2.31 (95 % CI: 1.46-3.68) and 1.04 (95 % CI: 0.61-1.77) in the first and second 4-month period, respectively adjusted to baseline values. There was an increase in unexpected ADR reporting (RR 2.06, 95 % CI 1.19-3.55). Pharmacovigilance educational interventions that have proved effective can be successfully applied in different geographical areas. A high baseline notification rate could account for the educational program having a moderate effect.

A multicentre, prospective, randomized, controlled study to evaluate the use of a fibrin sealant as an adjunct to sutured dural repair

Background. Obtaining intra-operative watertight closure of the dura is considered important in reducing post-operative cerebrospinal fluid (CSF) leak. The purpose of this study was to evaluate a fibrin sealant as an adjunct to sutured dural repair to obtain intra-operative watertight closure in cranial neurosurgery. Methods. This randomized, controlled multicenter study compared a fibrin sealant (EVICEL® Fibrin Sealant [Human]) to sutured dural closure (Control). Subjects underwent supratentorial or posterior fossa procedures. Following primary dural repair by sutures, the closure was evaluated for intra-operative CSF leak by moderately increasing the intracranial pressure. If present, subjects were randomized to EVICEL® or additional sutures (2:1 ratio), stratified by surgical approach. Following treatment, subjects were successful if no CSF leaks were present during provocative challenge. Safety was assessed to 30 days post-surgery, including incidence of CSF leakage. Results. One hundred and thirty-nine subjects were randomized: 89 to EVICEL® and 50 to Control. Intra-operative watertight closure was achieved in 92.1% EVICEL®-treated subjects versus 38.0% controls; a treatment difference of 54.1% (p < 0.001). The treatment differences in the supratentorial and posterior fossa strata were 49.1% and 75.7%, respectively (p < 0.001). The incidence of adverse events was similar between treatment groups. No deaths or unexpected serious adverse drug reactions were reported. CSF leakage within 30 days post-operatively was 2.2% and 2.0% in EVICEL® and control groups, respectively. In addition, 2 cases of CSF rhinorrhoea were observed in the EVICEL® group. Although not associated with the suture line where EVICEL® was applied, when combined with the other CSF leaks, the observed leak rate in the EVICEL® group was 4.5%. Conclusions. These results indicate that EVICEL® is effective as an adjunct to dural sutures to provide watertight closure of the dura mater in cranial surgery. The study confirmed the safety profile of EVICEL®.

Effectiveness, tolerability and acceptance of an oral estradiol/levonorgestrel formulation for the treatment of menopausal complaints: a non-interventional observational study over six cycles of 28 days

Background: Use of hormone therapy for menopausal complaints is a subject of controversy and increased uncertainty and concerns. This non-interventional study aimed to investigate a marketed oral formulation containing 1 mg estradiol and 0.04 mg levonorgestrel for continuous treatment of menopausal symptoms for approximately 6 months in women visiting gynecological practices in Germany.Methods: Changes in the menopause rating scale (MRS) total and sub-domain scores after three and six 28-d cycles served as primary endpoint. Skin- and hair-related complaints, quality of sexual life and subjective satisfaction with the treatment were assessed. Adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding were evaluated.Results: MRS scores improved significantly above 5 points of clinical relevance as compared to baseline (n = 736, p < 0.0001). Skin- and hair-related symptoms abated; quality of sexual life improved. AEs were registered in 9.9% of the participants. No unexpected ADRs were reported. Bleeding episodes consistently decreased; >75% of the subjects were amenorrheic throughout the study. Medication's effectiveness and tolerability was rated very good/good by >80% of the participants, who also continued treatment.Conclusion: This estradiol/low-dose levonorgestrel formulation safely alleviates menopausal symptoms in peri- and postmenopausal women with add-on benefits regarding dermatological and sexual life complaints.

The use of Instanyl® in the treatment of breakthrough pain in cancer patients: a 3-month observational, prospective, cohort study

PurposeInstanyl® (intranasal fentanyl spray) is a novel treatment for breakthrough pain (BTP) in cancer patients. It has shown a rapid onset of pain relief in clinical trials. This study examines the use of Instanyl® in real-life settings.MethodsA 3-month observational, prospective, cohort study of cancer patients with BTP receiving Instanyl® (50, 100, or 200 μg) under routine clinical practice. Data were collected at three time points corresponding with routine clinic visits – baseline, Week 4, and Week 13. Primary outcomes: success of titration and maintenance dose after titration. Secondary outcomes: change in maintenance dose of Instanyl® and level of background pain medication; Brief Pain Inventory—Short Form (BPI-SF) and Patient Treatment Satisfaction Scale (PTSS) scores; adverse drug reactions (ADRs).ResultsTitration with Instanyl® was successful in 84.5 % of 309 patients; most patients were titrated at the lowest dose (50 μg). The majority showed no change in maintenance dose, with little change in the level of background pain medication. BPI-SF and PTSS scores significantly improved from baseline to Week 4. The main reason for terminating Instanyl® was death, as expected due to the underlying disease; incidence of ADRs was low and no fatal ADRs were reported.ConclusionsIn a real-life group of cancer patients with disease progression, Instanyl® was titrated successfully at doses <200 μg in the majority of patients, requiring only one dose, with no further change in maintenance dose. Pain severity, impact of pain on daily life, and treatment satisfaction significantly improved with Instanyl® treatment. No unexpected ADRs occurred.

Off‐label and unlicensed drug use among neonatal intensive care units in Southern Italy

Many drugs used for neonates are unlicensed or off-label. An increased risk of medication errors and unexpected adverse drug reactions is associated with their use. This risk is even higher in preterm newborns, because of their physiological immaturity and the exposure to many different medicines. The objective of this study was to evaluate the use of unlicensed or off-label drugs in eight tertiary-level neonatal intensive care units (NICU) from two different southern Italian regions. All drugs prescribed to newborns admitted to each NICU, during 1 month of observation, were recorded and classified as licensed, unlicensed or off-label, according, respectively, first, to their license status and, then, their indications, dose, treatment route, and duration of treatment specified in each specific marketing authorization. A total of 126 newborns were treated with at least one drug during the observation period. A total of 483 prescriptions referred to 87 different drugs, classified as licensed, unlicensed or off-label. Each newborn was exposed to three (median) different drugs; 88.6% were licensed and 11.4% unlicensed (range, according to different NICU, 1.9-26.7%). Among licensed drugs, 37.4% were used as off-label (range, 27.3-53.4%). The use of unlicensed or off-label drugs use is common practice in NICU, with wide variation in local policies and newborn characteristics. Well-designed and -conducted pharmaceutical studies in newborns are needed to increase the number of licensed drugs, thereby reducing any risk for patients due to over- or under-treatment, and also legal issues for clinicians.

Intestinal levodopa infusion: the Belgian experience

Data concerning efficacy, safety, and patient satisfaction of levodopa/carbidopa intestinal gel (LCIG, Duodopa, AbbVie, Wavre, Belgium) infusion in routine clinical practice were needed to maintain reimbursement of the drug in Belgium. Patients with advanced Parkinson's disease in 27 neurology centers across Belgium were included. Of 100 patients who underwent naso-intestinal (NI) evaluation with LCIG, 67 received permanent treatment with LCIG via percutaneous endoscopic gastrostomy and jejunal tube (PEG/J). Efficacy was evaluated at baseline (on levodopa) and during a follow-up (FU) visit (on LCIG) using the Unified Parkinson's Disease Rating Scale (UPDRS) IV. Patient appraisal of the Duodopa system was evaluated using a visual analog scale for therapy compliance, user-friendliness, and global appreciation. Safety was assessed by reporting suspected adverse drug reactions (ADRs) and medical device-related complaints. FU evaluations were conducted in 37 patients. Significant improvement at FU was observed for motor complications (UPDRS IV) as the mean change from baseline to FU was -6.3 (95 % CI -8.1 to -4.5). Patient appraisal showed high scores for hospital delivery, user-friendliness, and patient global appreciation, as well as family appreciation of the system on daily life. Few ADRs and system malfunctions were reported, with no unexpected ADRs. In conclusion, the symptoms and impact of Parkinsonism improved markedly when LCIG PEG/J was initiated.

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: Postmarketing surveillance report of 7740 patients

Objectives. To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX).Methods. Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein.Results. Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment.Conclusion. Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients.

Study Design

The primary objective of the study—to clarify whether PRISCUS list medications are more commonly associated with adverse drug reactions (ADRs) than other medications—has been confirmed by the authors. But this seems not convincing due to the questionable primary goal, the prefered study design and some classifications being missing or misleading. Regarding the primary goal of the study: If the intention had been to provide an answer to the primary question it would have sufficed to study the frequency and severity of ADRs after administration of PRISCUS drugs (PDs) versus non-PRISCUS drugs in patients older than 65 with identical indications. In addition to the over-65s (n=351) however, 401 subjects younger than 65 were included. If the intention was to find an answer to the question of whether PDs are less well tolerated by older patients than by younger patients, then this comparison would have been the correct one to confirm the statement that older patients react more sensitively to PDs than younger ones—the indication being the same, obviously. Regarding the study design: The authors favored accidentally collected data from a cohort of patients in an emergency unit over a prospective, randomized controlled comparative study. The populations (under comparison) were of different sizes and inhomogeneous: in patients aged 65 or older, the most commonly observed disorders were circulatory disorders (35%) and gastrointestinal disorders (10.5%); In patients younger than 65, circulatory disorders were present only in 17.7% of cases, and psychological/behavioral disorders occurred in 10.2%. This means that medication therapy would be different in both compared groups, something that was not explained anywhere in the article. In total, only 149 patients with ADRs were evaluated. Regarding the classification: Medication errors (caused by the physician or non-compliance) cannot be subsumed into ADRs. In order to classify ADRs, information on severity/risk is required, especially for the comparison between PRISCUS drugs and non-PRISCUS drugs. The category “unexpected ADRs” is lacking. Did such reactions not occur? Of interest, albeit uncommented, is the fact that in the patient population under study, medication errors occurred in more patients (n=166) than adverse drug reactions (n=149). A further surprising result (disconcerting aspect) is (in) the drastic increase in medication errors in 90 patients between the age of 70 and 89. In conclusion: Medication therapy will have to be improved, especially for populations at risk.

Switching From Originator to Biosimilar Human Growth Hormone Using Dialogue Teamwork: Single-Center Experience From Sweden

IntroductionA new treatment plan was implemented at Skåne University Hospital, on economic grounds, for children requiring recombinant human growth hormone (rhGH) treatment. This involved switching patients from treatment with originator rhGHs to treatment with a biosimilar rhGH, somatropin (Omnitrope®), using a Dialogue Teamwork approach. The feasibility of using this approach to implement the switch of treatment was assessed, as well as the impact of the switch on treatment efficacy and cost of therapy.MethodsAs part of the Dialogue Teamwork approach, patients/parents received several opportunities for dialogue and sources of information, including discussions with the Head of Department, the responsible physician and a specialized endocrinology nurse. Height and height standard deviation score (HSDS) data were plotted for each individual patient (N = 98). A modeling approach was also used, to predict growth after switching to biosimilar rhGH; the predictions were then compared to the actual observed height after the switch. Costs to the clinic of rhGH therapy were calculated between May–August 2009 and May–August 2012.ResultsOf the 102 patients offered the switch, 98 accepted. Height and HSDS data indicated there was no negative impact on growth velocity after the switch to biosimilar rhGH. Modeling demonstrated that observed growth following the switch was consistent with predicted growth based on data before patients were switched. There were no reports of serious or unexpected adverse drug reactions following the switch to biosimilar rhGH. Following the switch, the cost to the clinic of rhGH treatment decreased from approximately 6 million SEK (May–August 2009) to approximately 4 million SEK (May–August 2012). This corresponds to an annual saving of 6 million SEK (€650,000).ConclusionPatients were successfully switched from originator to biosimilar rhGH (somatropin), with no negative impact on growth, and no serious or unexpected adverse drug reactions. The switch from originator to biosimilar rhGH is associated with substantial cost savings.

Updating the French Method for the Causality Assessment of Adverse Drug Reactions

The Imputability Working Group (CRI) updated the French drug reaction causality assessment method. This tripartite group is made up of staff from the French network of regional pharmacovigilance centres, pharmaceutical companies, and the French National Agency for the Safety of Medicines and Health Products (ANSM). After reviewing the strengths and weaknesses of the previous method, several ideas for improvement were proposed: a better-worded and more discriminating scale for certain chronological and semiological criteria, a larger scale for the intrinsic score (increased from 5 to 7 levels), a new bibliographical scale to differentiate between expected and unexpected adverse drug reactions, and a new informativeness scale.

Safety Information From Spontaneous and Literature Adverse Reaction Reports: A Comparison.

Marketing authorization holders should report adverse drug reactions (ADRs) derived from spontaneous case reports and literature for their medicinal products to competent authorities. Yet the difference in quality of data from both sources has never been analyzed. To this end, YES Pharmaceutical Development Services in cooperation with the German Medicines Manufacturers Association has conducted an analysis examining more than 25,100 spontaneous and literature cases that occurred between 2007 and 2008. Reporting rates of ADRs for specific drug substances (DSs), expectedness, and the system organ class (SOC) referred to were examined. It was found that the distribution of ADRs to specific SOCs differs between both groups for selected DSs. For more than 37% of the DSs being evaluated, a difference of 10% or more regarding reporting rates of unexpected ADRs was observed between both groups. These findings underline the substantial importance of regular literature reviews in addition to the spontaneous reporting system for a sufficient safety assessment of medicinal products.

Ayurveda Medicine for the Treatment of Parkinson’s Disease

In most western countries, the symptomatic management of Parkinson's Disease (PD) is usually achieved with medicinal products including levodopa (LD), dopamine agonists, MAO-B inhibitors, COMT inhibitors, antimuscarinics and amantadine. The control of the quality of the production of such medications is strict and the assessment of the benefit-risk ratio of these interventions is regulated by official recommendations which follow an evidence-based approach. Ayurveda Indian medicine has used Mucuna Pruriens (MP) for the treatment of PD since ancient times. MP includes LD as an active moiety, among many others. A literature search was conducted between 1978-2012 with the keywords Parkinson's disease, ayurveda or mucuna pruriens. MP antagonized the effects of 6OHDA lesions in rats and when administered chronically it showed lower dyskinetic potential compared to L-DOPA. MP also reduced Parkinsonian symptoms in an MPTP treated monkey with less dyskinesias compared to L-DOPA. Four clinical trials of MP for PD treatment were found. Initially they were open-label, uncontrolled studies, suggesting that MP might reduce parkinsonism severity. One double-blind randomized crossover study was conducted in 8 PD patients, employing acute challenges of levodopa or MP. It showed that the effect of MP had a faster onset than LD, with shorter latencies to peak and increased on-time. No other medium-term (i.e., 6 months) randomized-controlled trials (RCT) are available. According to the MDS EBM taskforce working procedures, an intervention is considered as efficacious when there is at least one high quality randomized controlled trial (RCT) showing a positive effect on studied outcomes with no conflicting data from other RCTs. Based on these premises, there is insufficient evidence to conclude the efficacy of MP in the treatment of PD. Thus its use in clinical practice remains open to investigation. It must also be emphasized that various MP formulations can be used, raising concerns about their quality, which is difficult to control, as regulation is limited. Impurities or variations in active moieties, can lead to unexpected adverse drug reactions. In conclusion, the use of MP in PD treatment remains open to investigation and thus cannot be recommended for clinical use.

Safety of Attention-Deficit/Hyperactivity Disorder Medications in Children: An Intensive Pharmacosurveillance Monitoring Study

Our intensive pharmacosurveillance monitoring program was performed to increase the number of adverse drug reactions (ADRs) recorded in the Italian spontaneous reporting database, and to systematically collect more thorough data about atomoxetine (ATX) and methylphenidate (MPH) safety in the pediatric setting. From September 2007 to October 2010, 1841 youth were enrolled in the Italian Attention- Deficit/Hyperactivity Disorder Register, but we report here on the 76 children from the five Reference Prescription Centers in Campania, an Italian region where we administered our systematic adverse event checklist. Among our cohort, 68 children received a prescription of ATX and 8 received a prescription of MPH. Most children were male and between 10 and 13 years of age, had a diagnosis of attention-deficit/hyperactivity disorder-combined (ADHD-C) and had learning disability as the main comorbidity. Most ADRs reported to the Italian spontaneous reporting database occurred in patients from Campania. Twenty-five experienced at least 1 ADR for a total of 40 ADRs reported to the Italian drug agency. Most ADRs were common and not serious, and resolved completely. Weight loss was the most frequently reported ADR. Only two ADRs were unexpected and only one was uncommon. Sixteen ADRs resulted in permanent drug withdrawal. Based on the Naranjo algorithm, 25 ADRs were considered "probable" and 15 were considered "possible." Although our data provide reassurance of the safety of ATX and MPH, several unexpected or uncommon ADRs (hepatomegaly, suicidal ideation, weight gain, or drug interactions) were identified by our intensive pharmacosurveillance monitoring program. Our results show that an intensive pharmacosurveillance monitoring program that involves pharmacovigilance centers and clinicians can improve the collection of information on drug safety in children.

A new pharmaceutical form of leuprorelin acetate for the treatment of advanced prostate cancer: Clinical experience from a non-interventional study

Purpose: A new pharmaceutical form of leuprorelin acetate has been developed for the treatment of advanced prostate cancer. This product is a rod-shaped implant in which the active substance is dispersed homogeneously in a lactic acid polymer. The implant is administered once every 3 months by subcutaneous injection into the anterior abdominal wall, where it is hydrolytically degraded and the active substance is continually released. Here, we report data from a large noninterventional observational study of this implant conducted inGermany. Methods: Included patients were men diagnosed with advanced hormone-dependent prostate cancer and receiving, or about to start, treatment, with the 3-month implant. A total of 1148menwere analysed. The start of the observational period was the date of the first administration of the 3-month implant. Baseline demographic data and relevantmedical historywere collected at visit 1. Thepatients returned for two observational visits at 3-month intervals; additional injections could be given at these visits according to the clinical judgement of the treating physician. Themain objective of the study was to assess the safety profile of the 3-month implant in routine clinical practice. The incidence and frequency of the expected adverse drug reactions (ADRs) were assessed, and unexpected ADRs identified. At visits 2 and 3, physicians assessed treatment success and patients assessed the tolerability of the implant using a 5-point scale (very good, good, satisfactory, poor, and very poor). The efficacy of the medication was assessed from PSA measurements made during the routine medical examinations. Results: The mean age of the patients was 74.6 years and the mean duration of their prostate cancer was 22 months. Metastases were present in 242 patients. Overall, the type and incidence of ADRswere as expected for this product and the LHRH agonist class. Expected ADRs were experienced by 70.8% of patients, with hot flushes (554 patients; 48.3%) and increased sweating (383 patients; 33.4%) themost frequent. Other expected ADRs reported included loss of potency (33.2%), loss of libido (31.6%) and weight gain (25.5%). Only 15 patients (1.3%) experienced unexpected ADRs. In only 2 patientswere these considered to be drug-related; one patient experienced erysipelas and abdominal wall abscess after the second injection, and one patient experienced constipation and a slight decrease in haemoglobin after the first injection. Four patients died during the observation period; no death was considered to be related to study treatment. Physicians assessed treatment success as very good/good/satisfactory in more than 98% of patients at visit 2 and visit 3. More than 98% of patients assessed tolerability of the implant as very good/good/satisfactory at visit 2 and visit 3. Mean PSA decreased by more than 80% between visit 1 and visit 2, with a further slight decrease between visits 2 and 3. Conclusion: The new 3-month implant of leuprorelin acetate was well tolerated by patients. The type and incidence of ADRs were as expected for this product and the LHRH agonist class. PSA control was achieved in the majority of patients.

Comparative evaluation of adverse drug reaction reporting forms for introduction of a spontaneous generic ADR form

Despite comprehensive and stringent phases of clinical trials and surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after the drug is marketed. ADR reporting is an important aspect of an efficient and effective pharmacovigilance program. Although Medwatch, Yellow Card, CDSCO form, etc. are the protocol forms of ADR collection and reports, a number of countries design and use their respective ADR forms. This review compares similarities and dissimilarities of 13 ADR forms of countries representing their geographical location. This study extracted 73 data elements mentioned in 13 different ADR forms. Only 13 elements were common. An ADR form of Malaysia and Canada covers the highest number of data 43, while Brazil falls to the opposite end with a number of 17 data elements in lieu with the Generic ADR Form. The result of this review highlights 58 data elements of the proposed generic ADR form which ensures that requisite reporting information essential for correct causality assessment of ADRs are included. The proposed “Generic ADR form” could be adopted worldwide mandatorily for reporting any/all ADRs associated with marketed drugs.