Risk minimization programs are interventions mandated by regulatory agencies to ensure that benefits of pharmaceutical products outweigh risks. Many regulatory agencies require programs be evaluated for effectiveness; however, the quality of evidence has limited the ability to definitively determine if programs improve drug safety. The aim of this systematic review was to assess and describe the current status of reporting on the effectiveness of pharmaceutical risk management programs. Peer-reviewed articles published between January 2012 and December 2018 were selected from three online databases (MEDLINE, PubMed, Embase). Eligible studies reported on effectiveness evaluations of mandated risk minimization measures (beyond labeling) and were written in English. Two reviewers independently examined 2744 titles of articles and 52 full articles were included. Forty-eight sources of gray literature from conference abstract presentations and publicly available regulatory documents were also included. Key opportunities for improvement in reporting included the provision of information regarding (1) selection, design, and testing of risk minimization measures, (2) implementation of programs, (3) process and outcome metrics, including the extent to which programs reached the intended audience, were integrated into the target healthcare settings, or were sustained over time, and (4) burden of the program on the healthcare system and implications for patient access. Gaps in reporting of risk minimization program evaluation studies were identified. Addressing gaps will help build the evidence base regarding risk minimization initiatives, as well as ensure that programs are maximally effective and minimally burdensome on the healthcare system, and do not unduly interfere with patient access to the medicine.

Quality of Reporting on the Evaluation of Risk Minimization Programs: A Systematic Review

Purpose This study evaluated the effectiveness of risk minimisation measures (RMMs) implemented following the 2014 referral for valproate in Europe. Methods Cross-sectional survey was conducted over 2-month period in 2016 among physicians who prescribed valproate in France, Germany, the United Kingdom, Spain and Sweden. The web-based questionnaire included five endpoints to evaluate physicians' knowledge on (a) prescribing valproate only for epilepsy and bipolar disorder in women if other treatments were ineffective or not tolerated; (b) ensuring supervision by experienced physicians while treating these conditions; (c) considering alternative treatments for women planning pregnancy, regular review of treatment needs and re-assessing the benefit-risk balance in women and girls reaching puberty; (d) informing patients about the risks of taking valproate during pregnancy and (e) advising women on effective contraception during their treatment. Results Among 1153 physicians, 95.5% responded prescribing valproate for epilepsy and bipolar disorder in women only if other treatments are ineffective/not tolerated; 66.5% supervised while treatment; 76.6% considered alternative treatments for women planning pregnancy; 92.1% informed patients about the risks of taking valproate during pregnancy and 94.4% advised patients on the use of effective contraception during its treatment. Overall, 25.8% physicians recalled receiving both educational material (EM) and Dear Healthcare Professional Communication (DHPC). All endpoint rates were higher for physicians who acknowledged receipt of both DHPC and EM compared to physicians who did not receive them. Conclusions Although results varied across geography and physician speciality, majority of physicians had good knowledge about the indication and safety aspects of prescribing and using valproate.

Effectiveness of risk minimisation measures for valproate: A cross-sectional survey among physicians in Europe.

Aim This study assessed the linearity of pharmacokinetics (PK) of
 trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on
 therapy for stable angina pectoris) and measured its renal elimination, safety,
 and tolerability in healthy subjects. Methods This was a randomized, open-label, single-ascending dose study in
 healthy subjects. Subjects were administered with a single dose of 35, 70, or
 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic
 evaluations and safety analysis were performed before the first dose and till
 48 h post-first dose. Results Following administration of 35, 70, and 105 mg
 TMZ-modified release; the Cmax (mean±SD) was 79.32
 (±23.08), 153.17 (±23.08), and 199.67 (±23.08)
 ng/mL, the Tmax was 5.42 (±0.49), 4.51
 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75
 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h,
 AUC(0-inf) was 1116.89 (±378.35), 1838.39
 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR
 was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24)
 L·h−1 and CL/F was 33.69 (±8.51),
 38.85 (±6.15), and 42.74 (±7.10)
 L·h−1, respectively. Slope estimates for
 AUC(0-inf), AUC(0-t), and Cmax were less
 than 1. Corresponding 95% CI of the slope for the AUC parameters
 excluded 1, indicating that the deviation from dose-proportionality was
 statistically significant. Corresponding 95% CI of the slope for
 Cmax included 1, indicating that the less than dose-proportional
 increase in Cmax was not statistically significant. No significant
 adverse events were observed. Conclusion Substantial deviation from a dose-proportional increase in
 AUC(0-inf) and AUC(0-t) suggested a non-linear PK for
 TMZ-modified release. Single dose of TMZ-modified release was well tolerated and
 safe.

/pdf/single-ascending-dose-study-to-assess-pharmacokinetic-2kqdyh0cwp.pdf

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects

BACKGROUND
Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO).


OBJECTIVE
Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-b-Ketoacyl-CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer.


RESULTS
Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs.


CONCLUSION
We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.

PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal.

An association between trimetazidine (TMZ), an anti-anginal drug, and parkinsonism has been reported in a number of studies. However, evidence from studies with long-term follow-up and better validity is lacking. We investigated the risk of TMZ-associated parkinsonism, specifically the incidence rate, cumulative dose-response relationship, and combined effects with other parkinsonism-inducing medications. This propensity score-matched retrospective cohort study was conducted using 14-year health insurance claims data in South Korea. The risk of parkinsonism was evaluated using multivariate Cox proportional hazard regression analysis, adjusted for comorbidities and concurrent medications. A total of 9712 TMZ users and 29,116 matched non-TMZ users were included. TMZ users had a significantly higher incidence rate of parkinsonism than non-TMZ users (9.34 vs. 6.71 per 1000 person-years; p < 0.0001). TMZ use significantly increased the risk of parkinsonism (adjusted hazard ratio = 1.38; 95% confidence interval = 1.26-1.51). Increased risks were observed with accumulated doses of TMZ, as well as concurrent use of other parkinsonism-inducing medications. The findings indicate that TMZ use significantly increases the risk of parkinsonism in the South Korean population. Closer monitoring should be considered for TMZ users, especially for those who are older, using TMZ at high cumulative doses and other parkinsonism-inducing medications.

https://www.mdpi.com/1660-4601/17/19/7256/pdf

Trimetazidine Use and the Risk of Parkinsonism: A Nationwide Population-Based Study.

PURPOSE In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open‐label multiple‐dose study

What is known and objective The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). Methods This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). Results and discussion During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). What is new and conclusion This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain

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Papers

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open‐label multiple‐dose study

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain