Venous thromboembolism in myelodysplastic syndrome patients receiving lenalidomide: results from postmarketing surveillance and data mining techniques.

BACKGROUND AND OBJECTIVES: Multiple myeloma treatment with lenalidomide-based regimens is associated with risk of venous thromboembolism (VTE), particularly during concomitant use with erythropoiesis-stimulating agents (ESAs). The risk of VTE in myelodysplastic syndrome (MDS) patients treated with lenalidomide is not well characterized and the background risk in untreated patients is not known. This study set out to determine the reporting rate of VTE in MDS patients on lenalidomide in the two years of postmarketing experience in the US, and to investigate whether there is a disproportional signal of VTE in MDS patients on lenalidomide by screening the US FDA Adverse Event Reporting System (AERS) safety database. METHODS: The MDS population exposed to lenalidomide was obtained from RevAssist, the company's proprietary restrictive distribution programme. VTE reports were identified from the company's postmarketing surveillance safety database. The FDA AERS database was used for disproportionality analysis, and signal scores computed using three algorithms: multi-item gamma Poisson shrinker (MGPS), proportional reporting ratio (PRR), and reporting odds ratios (ROR). RESULTS: A total of 7764 MDS patients were prescribed lenalidomide during the first two years of commercial use in the US. VTE representing deep vein thrombosis and pulmonary embolism was reported in 41 patients, a reporting rate of 0.53%. The computed signal scores did not exceed the statistical threshold for identification of a significant disproportional signal for VTE in MDS reports involving use of lenalidomide without concomitant use of ESAs. However, a disproportional signal of VTE was detected in MDS reports where lenalidomide was concurrently used with ESAs. CONCLUSION: The VTE reporting rate for MDS patients receiving lenalidomide during the first two years of postmarketing exposure was low (0.53%). Disproportionality analysis demonstrated a statistically meaningful association of VTE with lenalidomide concomitantly used with ESAs in MDS patients, but the association was not statistically significant when lenalidomide was used in the absence of ESAs.

RevAssist: a comprehensive risk minimization programme for preventing fetal exposure to lenalidomide.

Lenalidomide (Revlimid) is an immunomodulatory drug and an analogue of thalidomide, a known teratogen. To prevent fetal exposure, in the US lenalidomide is available only under a special restricted distribution programme called RevAssist. Under this risk minimization programme, only prescribers and contract pharmacies registered with the programme are able to prescribe and dispense the product. Patients must be advised of, agree to and comply with the requirements of the RevAssist programme in order to receive lenalidomide through a registered prescriber. A total of 15 584 patients were registered in the RevAssist programme during the first year lenalidomide was on the market. There were four reports of false-positive beta-human chorionic gonadotrophin measurements in patients aged 43-57 years. Mandatory patient and prescriber surveys have shown discrepant responses that were resolved by risk management intervention specialists 99% of the time. The voluntary patient surveys have shown understanding of the risks of lenalidomide use and of behaviours necessary to minimize risks in >95% of females of childbearing potential and adult males. To date, there have been no reports of pregnancy in female patients or female partners of male patients. The pharmacy audit findings showed compliance with RevAssist was high. Although RevAssist is labour-intensive, time-consuming and costly, it continues to be effective in preventing fetal exposure to lenalidomide.

Effectiveness of Risk Evaluation and Mitigation Strategies (REMS) for Lenalidomide and Thalidomide: Patient Comprehension and Knowledge Retention.

INTRODUCTION: The effectiveness of patient education activities conducted within the lenalidomide and thalidomide risk evaluation and mitigation strategies (REMS) programs was evaluated by measuring understanding of serious risk and safe-use messages. METHODS: Results from mandatory knowledge, attitude, and behavior surveys and voluntary patient surveys completed between June 2012 and June 2013 were analyzed, and responses to questions relating to compliance with birth control measures and understanding of safe-use messages are presented by patient risk category. RESULTS: In total, 73,645 patients were enrolled into the REMS programs for lenalidomide and thalidomide and completed mandatory surveys prior to medication dispense. Of these, 2790 (3.8%) completed an additional voluntary survey. Among voluntary survey participants, for all patient pregnancy risk categories, reported compliance with birth control requirements was above 90% when starting therapy and at follow-up. At the beginning of therapy, complete compliance was 96.3%; 3 months later it was 96.4%. Patient understanding of safe-use messages was very high in all pregnancy risk groups, notably for messages repeated at each physician visit. Overall, 98.2% of patients knew that lenalidomide and thalidomide could cause birth defects, which is part of the repeated educational messaging. In contrast, 87.1% recalled that unused product should be returned to their healthcare professional, which is not included in repeated messaging. CONCLUSION: The lenalidomide and thalidomide REMS programs enhance patient understanding of safe-use messages, resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure to these known and potential human teratogens. Overall compliance was maintained after 3 months of follow-up and throughout therapy.

The Effectiveness of an Educational Brochure as a Risk Minimization Activity to Communicate Important Rare Adverse Events to Health-Care Professionals.

INTRODUCTION: Educational brochures are an important tool for communicating risk to health-care professionals. It is important to evaluate the impact of any risk minimization tool to understand the effectiveness of the strategy. The objective of this study was to assess the effectiveness (i.e., respondents' awareness and understanding of the communication) of a targeted educational brochure distributed to health-care professionals (HCPs) as a risk minimization strategy for the communication of new rare and important adverse events (AEs). METHODS: A prospective, non-interventional, online survey was performed following distribution of a specifically designed brochure highlighting new and important adverse events to a targeted HCP population, consisting of known users of the target medicine, as represented by a commercial database. Predefined multiple-choice survey questions assessed overall HCP awareness of the brochure and understanding and retention of information in those HCPs who reported receiving the brochure. RESULTS: The educational brochure was sent to a total of 565 HCPs; 121 (21.4%) responded to the survey. The majority of respondents (95.0%) had previously prescribed or dispensed the target medicine. In all, 88 (72.7%) respondents said they had received the educational brochure, of whom 95.5% stated they had at least scanned the main points. More participants who had received the brochure (86.4% to 96.6%) answered the five individual survey questions correctly compared with those who did not (51.5% to 97.0%); this was significant for four out of five questions (P ≤ 0.005). Significantly more HCPs who received the brochure achieved the predefined pass rate (at least four of five questions answered correctly) compared with HCPs who did not receive the brochure (93.2% vs 57.6%, respectively; P = 0.000003). CONCLUSIONS: Distribution of targeted educational brochures may be an effective risk minimization strategy to raise HCP awareness of new rare and important AEs; educational brochures may also be an effective channel for sharing information on how these AEs can be best managed and on the importance and means of reporting AEs. FUNDING: Celgene Pty Ltd, Melbourne, Australia.

Teratogenic Drugs and Risk Management: An Implementation Assessment.

About half of all pregnant women are prescribed medication during their pregnancy, including drugs with teratogenic potential. There is a need to manage teratogenic risk and prevent fetal harm. In the US, risk management strategies may range from product labeling to the US Food and Drug Administration requiring a risk evaluation and mitigation strategy, including elements to assure safe use. The resources of these risk management controls on the health care system must be weighed against the benefits of preventing embryo-fetal exposure and birth defects. This article describes considerations for determining which risk mitigation strategies to use with teratogenic drugs and the challenges and opportunities to balance restrictions and burdens with the benefit of access to important drugs.

Managing the teratogenic risk of thalidomide and lenalidomide: an industry perspective.

Celgene has developed and operated pregnancy prevention programs since 1998 with the first approval of thalidomide in the US. With the development and marketing of lenalidomide, an analog of thalidomide, the company further advanced its risk management activities, which now cover several territories across the globe. To date, the program is a success in as much as it has minimized the risk of fetal exposure and subsequent development of fetal malformations. Nonetheless, the company understands the need to provide a mechanism for intervention and remediation when at-risk behaviors are identified, and this forms an integral part of the risk management processes. The implementation of the thalidomide and lenalidomide pregnancy prevention program partners patients, healthcare professionals, regulators and the company in a spirit of shared responsibility. This paper also presents the authors' experience and perspective on the challenges of managing a pregnancy prevention program, which at its core aims at ensuring that the product's benefits outweigh the risk of fetal exposure.

Finding patients eligible for antiretroviral therapy using TB services as entry point for HIV treatment.

OBJECTIVE: To estimate the proportion of antiretroviral therapy (ART) eligible adults (15-49 years) with tuberculosis potentially identifiable through tuberculosis services using a CD4 count below 350 cells/mm3 as cut-off value for ART initiation. METHODS: Using TB notification rate data, HIV seroprevalence data, and estimates of the size of the adult population (15-49 years) in 18 sub-Saharan African countries with an HIV seroprevalence of > 5%, calculations of the number of ART eligible adults with tuberculosis presenting to tuberculosis services were made. Assumptions were made on the tuberculosis notification rates in the age-group 15-49 years, the HIV-infected population with a CD4 count below 350 cells/mm3 and the relative risk of developing tuberculosis, and average duration from HIV infection to death. The probability of having a CD4+ count below 350 cells/mm3 given a diagnosis of tuberculosis was estimated using Bayes' theorem, and estimates of the number of patients with a CD4 count below 350 cells/mm3 identifiable through tuberculosis were made. The number needed to screen to identify one ART eligible patient through tuberculosis services was estimated for each country. RESULTS: ART eligible adults with tuberculosis potentially identifiable through tuberculosis services in the 18 countries ranged from 2% to 18% of the total HIV-infected adult population with a CD4+ count below 350 cells/mm3 and would average 10% of all such HIV patients. The number needed to screen to identify ART eligible patients through tuberculosis services ranged from 1.4 to 4.2, against 8.6 to 65.4 if adults aged 15-49 are randomly screened for low CD4 counts. CONCLUSION: Tuberculosis services are an important entry point for identifying ART eligible patients. Given that dually infected patients identified through tuberculosis services contributed to 10% of the HIV-infected adult population with a CD4 cell count below 350 cells/mm3 in the 18 sub-Saharan African countries, major efforts are required beyond the tuberculosis services in detecting patients that should benefit from ART. However, the low number needed to screen gives opportunity to use tuberculosis services in AIDS control and ART scaling-up programmes.