First-dose Observation Research Articles

Analysis of cardiac monitoring and safety data in patients initiating fingolimod treatment in the home or in clinic

BackgroundFingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative.MethodsCardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency.ResultsData were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as “very good,” and 7.6% rated their satisfaction as “good.” AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block.ConclusionsA substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.

P.068 Real world experience with Fingolimod in Canada

Background: The Gilenya® Go ProgramTM offers education and support services, including coordination of first dose observation (FDO) and follow-up contact to reinforce monitoring recommendations and compliance in fingolimod-treated relapsing-remitting multiple sclerosis (RRMS) patients. Methods: Data were analyzed for patients enrolled in the Canadian Gilenya® Go ProgramTM from March 2011 to January 2016. The retention to fingolimod therapy, reasons for treatment discontinuation and incidence of adverse events (AEs) during treatment are reported. Results: At data cut-off, 3956 patients had completed FDO; 3201 patients were being actively treated. Mean age at enrolment was 41.0 years; 74.9% patients were female. The overall fingolimod exposure was 7869 patient-years. Most recent previous therapies (n=3746) included interferons (43.3%) and glatiramer acetate (29.6%). Most common reasons for switching to fingolimod (n=3674) was lack of efficacy (31.8%). Retention to therapy at data cut-off was 81.3%. AEs (45.2%) were the most common reason (n=334) for treatment discontinuation and included low lymphocyte count/abnormal hematology values (13.8%), gastrointestinal disturbances (6.9%), and elevated liver enzyme levels (7.8%). Adherence to recommended ophthalmic examination was 92.4%. Conclusions: In real-world clinical practice in Canada, adherence to both fingolimod treatment and monitoring was high. The Gilenya® Go Program™ helps to meet the safety monitoring recommendations for fingolimod-treated RRMS patients.

Cardiac Safety Profile of First Dose of Fingolimod for Relapsing-Remitting Multiple Sclerosis in Real-World Settings: Data from a German Prospective Multi-Center Observational Study.

IntroductionFingolimod was the first oral therapy approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Due to its action on cardiac sphingosine 1-phosphate receptors, fingolimod is leading to a transient decrease in heart rate (HR) and the occurrence of rare and asymptomatic self-limited atrioventricular (AV) blocks. This German non-interventional clinical study aimed to assess the cardiac safety profile in RRMS patients during at least 6 h after the initial treatment or restart after interruption of fingolimod in real-world settings.MethodsThe GoCARD study (German National Health Authorities, BfArM, CFTY720DDE18, NIS334) was a prospective, multi-center non-interventional study which was conducted in neurological and other medical practices or hospitals, qualified to routinely assess electrocardiogram (ECG) findings. Data were collected through interviews, clinical evaluations (notably ECGs), and laboratory tests. Medical history, vital signs, and a 12-lead ECG were assessed before fingolimod administration. After the first dose, a 6 h ECG was performed and vital signs (blood pressure and HR) were measured hourly. The occurrence of bradycardia (HR ≤45 beats per minute [BPM]), AV blocks (2nd degree Mobitz type I or higher), and corrected QT interval (QTc) intervals was also documented.ResultsMore than 95% of physicians adhered to the cardiac monitoring recommendations. The observation of 217 patients in 42 study centers showed that while 35.9% of the patients had any cardiac risk profile, none of them experienced a bradycardia during the 6 h post-dose observation. Overall, only 1.8% of all patients displayed bradycardia (HR ≤45 BPM) during 6 h after treatment initiation. Moreover, in this cohort, none of the patients showed a new or persistent onset AV block (2nd degree Mobitz type I or higher) or QTc ≥500 ms.ConclusionAltogether, these data confirm that the first-dose observation after fingolimod initiation is usually uneventful (even in patients with pre-existing cardiovascular risk factors of this cohort) and that the rarely observed events remained asymptomatic and self-limited.FundingNovartis Pharma GmbH, Nürnberg, Germany.

Canadian Experience with Fingolimod: Adherence to Treatment and Monitoring.

The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc. A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-β agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination. The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians' and/or patients' perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.

The management and outcomes of fingolimod first dose cardiac monitoring in UK patients with relapsing-remitting multiple sclerosis

BackgroundPatients initiated on Gilenya (fingolimod) require cardiovascular monitoring for 6h after the first dose. Novartis has engaged an independent provider (Regent's Park Heart Clinics [RPHC]) to provide a first dose observation (FDO) service to UK neurologists. ObjectivesTo describe routinely-documented clinical observations (heart rate [HR], blood pressure [BP], cardiac rhythm [CR]) and outcomes from the RPHC fingolimod FDO service. MethodsPseudonymised data (clinical observations pre-dose and for 6h after the first dose and any requirement for extended monitoring) were collected retrospectively from RPHC records for the first 850 RPHC FDO episodes (undertaken Jul-2012 to Jan-2015). All episodes involved patients with relapsing-remitting MS who were initiated on fingolimod in routine National Health Service (NHS) clinical practice. ResultsIn 78% of FDO episodes the patient was female. Mean age at date of episode was 40.1 years. Mean HR was 72.7bpm (beats per minute) pre-dose, 64.3bpm at 5h (the lowest recorded HR) and 66.1bpm at 6h post-dose. New-onset heart block was observed in 2% of episodes (1.5% first-degree; 0.5% second-degree). The patient was discharged at 6 hours post-dose in 97% of episodes and required extended monitoring in 3%. In 5 episodes overnight monitoring was required. There were no episodes in which the patient required pharmacological intervention or temporary cardiac pacing. ConclusionsIn this real-world UK population fingolimod initiation was predominantly uneventful; clinical observations were similar to previous clinical trials.

Long-term cardiac safety and tolerability of fingolimod in multiple sclerosis: A postmarketing study.

Fingolimod is the first oral disease-modifying therapy approved for multiple sclerosis (MS). The risks associated with the use of fingolimod include cardiovascular adverse events (AEs). First-dose observation (FDO) is required for all patients for at least 6 hours. We describe FDO data and long-term cardiac tolerability in a cohort of fingolimod-treated relapsing MS patients. Two hundred and twelve patients started fingolimod 0.5 mg once daily. Before the first administration, all subjects had an electrocardiogram (ECG) with cardiologist interpretation. Following administration they were monitored for 6 hours and underwent a cardiac monitoring every 3 months. In this cohort, there was a heart rate reduction at the VI hour of 9.6 ± 8 beats per minute (P < .001). Fifty-four individuals (25.5%) presented an abnormal ECG during the 6 hours. We experienced 1 case (0.22%) of symptomatic second-degree atrioventricular block. The mean follow-up period was 1.5 ± 0.7 years. During this period, 1 patient showed atrial fibrillation that needed to be treated. We also observed 5 cases of persistent increase in blood pressure. This postmarketing study shows that fingolimod is well tolerated and tha tcardiologic AEs are generally self-limited in the long term.

A Swiss real world best practice experience in three different clinical settings of the 6 hour fingolimod first dose observation procedure.

BackgroundThe Swiss label of oral fingolimod (0.5 mg once daily) requires a 6-hour first dose observation (FDO) including an ECG prior to and 6 hours after the first intake but in comparison to other countries such as Austria, Australia and Canada there are no restrictions regarding the clinical settings of the FDO procedure in Switzerland. We present here our real-world experience of the 6 hour FDO procedure in three different clinical settings, following fingolimod treatment initiation. This is the first report on the FDO of fingolimod in these real-world clinical settings in Swiss patients with multiple sclerosis (MS).MethodsThis was a retrospective, multi-clinic, observational study of 136 patients with relapsing-remitting multiple sclerosis. Summary statistics have been used to present the data.ResultsOnly two patients (<1.5% [2/136]) experienced symptoms after the first dose of fingolimod. Atrioventricular conduction abnormalities were reported in 3% (4/136) of patients, which resolved spontaneously within 24 hours of treatment initiation. During the average 6.8 months follow-up, 96% (131/136) of the patients remained on therapyConclusionsThese findings support the safety and feasibility of FDO and tolerability of fingolimod in real-world clinical settings.

Initiating oral fingolimod treatment in patients with multiple sclerosis

Fingolimod, the first oral disease-modifying therapy (DMT) approved for the treatment of multiple sclerosis (MS) and the only sphingosine 1-phosphate receptor modulator approved for any disease state, represents an important addition to the expanding DMT options for patients with MS. In three large phase III clinical trials, fingolimod 0.5 mg reduced relapses by approximately half compared with either placebo or weekly intramuscular interferon β1a. The risks associated with the use of fingolimod include first-dose bradycardia, macular edema, and elevation of liver enzymes; fingolimod may increase the risk of infections, some serious in nature, and potentially cause fetal harm. Breakthrough disease or intolerance of injectable medications may be factors that influence the initiation of fingolimod. Identification of potential patients suitable for fingolimod treatment requires a thorough understanding of the potential risks and the particular fingolimod indication of the national authority. To minimize risk, recommended baseline assessments that should be made prior to fingolimod initiation include complete blood count, liver transaminase levels, total bilirubin levels, electrocardiogram (ECG), ophthalmologic examination, varicella zoster infection status, and for women, childbearing potential. First-dose observation is required for all patients for at least 6 h, with hourly pulse and blood pressure measurements and ECG before and 6 h after the first dose. In the European Union, continuous telemetry monitoring is recommended. Healthcare providers should be aware of the potential for symptomatic bradycardia and the need for continuous overnight ECG monitoring for those at higher risk for bradycardia. With experience in over 63,000 patients and over 73,000 patient-years of exposure in clinical trials and postmarketing use, the benefits and full safety profile of fingolimod continue to become better elucidated. This information will enable healthcare providers to initiate fingolimod in appropriately selected and screened patients with MS.

A cross-sectional survey of patient satisfaction and subjective experiences of treatment with fingolimod

BackgroundFingolimod is the first oral disease-modifying therapy indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses and delay the progression of physical disability caused by MS.ObjectiveTo obtain data from MS patients who have taken fingolimod regarding their treatment choice, first-dose observation (FDO) experience, and treatment satisfaction.MethodsPatients ≥ 18 years old with physician-diagnosed MS in the United States who had taken at least one dose of fingolimod for the treatment of MS were invited to complete a web-based survey, which captured information on the reasons for starting fingolimod, FDO experience, and treatment satisfaction as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM). A high TSQM scale score denotes high satisfaction.ResultsSurvey respondents (n = 380; 55% female) had a mean (standard deviation) age of 39.8 (12.6) years, and a mean (standard deviation) duration of MS of 9.8 (10.3) years. Overall, more than 80% of patients reported the first dose was moderately/very/extremely manageable, convenient, and easy to take. Although 80% of patients reported experiencing a side effect with the first dose, most were highly tolerable and only eleven patients (2.9%) reported they were “Not at all” satisfied with the FDO experience. TSQM scale scores were highest for the side effect (79.4), followed by convenience (71.7), effectiveness (70.1), and global satisfaction (68.9) domains; relatively higher scores were observed among treatment-experienced patients. Both treatment-naïve and treatment-experienced patients indicated physician recommendation as the primary reason for starting fingolimod. Among treatment-experienced respondents (n = 273), 58% reported that their first choice for MS treatment would be fingolimod if selecting today.ConclusionMost fingolimod patients were satisfied with their FDO experience. Satisfaction with fingolimod was high and observed higher among treatment-experienced compared to treatment-naïve patients. Additional research is needed to understand key clinical and medication attributes underlying treatment satisfaction with fingolimod and other disease-modifying therapies.

Early tolerability and safety of fingolimod in clinical practice

BackgroundFingolimod is approved by the U.S. Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. Several screening studies and a first-dose observation (FDO) period are recommended due to adverse effects observed in clinical trials. ObjectiveThe objective of this study is to describe the early experience with fingolimod, including startup, tolerability and safety in a large academic multiple sclerosis (MS) center. MethodsPatients prescribed fingolimod from September 2010 to July 2011 were identified through electronic medical records. Demographics, MS disease history, pre-treatment screening studies, FDO experience during shared medical visits and three month follow-up data were analyzed. ResultsThree hundred ninety-one patients were prescribed fingolimod of whom 317 started the medication and were included in the analysis. Fingolimod was most frequently used in relapsing remitting MS (n=256, 80.8%) and was prescribed as a first-line agent in 11 cases (3.5%). FDO was uneventful in 308 patients (96.8%). Adverse events during FDO were self limited and included symptomatic bradycardia (n=3), chest tightness (n=2) and hypertension (n=1). Fingolimod was discontinued in 30 patients (9.5%) at three months. Adverse effects leading to discontinuation by more than one patient included headache (n=4), macular edema (n=3), nausea (n=3) and hypertension (n=2). ConclusionsFingolimod was well tolerated during FDO and adverse events were self limited. The shared medical visit is an appropriate setting for FDO. Adverse effects were similar to those described in clinical trials but the discontinuation rate was higher.

Cardiovascular Effects and Safety of Fingolimod in Clinical Practice (P04.138)

Objective: To describe the cardiovascular safety and tolerability of fingolimod in a clinical/academic practice. Background Fingolimod is approved by the FDA for relapsing multiple sclerosis (RRMS). Bradycardia and slowing of AV conduction were observed with fingolimod initiation in clinical trials. Screening electrocardiogram (EKG) and a first dose observation (FDO) period is recommended in all patients starting this medication. Design/Methods: Patients starting fingolimod from December 2010 to August 2011 were identified through the electronic medical record database. Demographics, cardiovascular history, screening EKG, cardiology consultation notes, FDO experience and 3 month follow-up data were retrieved and tabulated. Results: A total of 318 patients were identified. A history of hypertension was present in 30 (9.4%) of patients and a history of cardiac disease was present in 8 (2.5%) patients. Betablockers, calcium channel blockers, and digoxin were used by 3.7%, 2.8%, and 0.6% of patients respectively. Pretreatment EKG studies were available in 300 (94.3%) patients and were abnormal in 80 (25.2%) cases. Cardiology consultation was requested in 33 (10.4%) patients and use of fingolimod was cleared for all. During FDO mean heart rate change was -11.5 bpm (p Conclusions: Screening EKG showed abnormalities in a quarter of patients starting fingolimod, and identified patients at risk for symptomatic bradycardia. Fingolimod was well tolerated and no severe or serious cardiovascular adverse effects were encountered during FDO. Disclosure: Dr. Bermel has received personal compensation for activities with Astellas, Biogen Idec, Novartis, and Teva Neuroscience as a consultant and/or speaker. Dr. Ontaneda has nothing to disclose. Dr. Hara-Cleaver has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., and TEVA Neuroscience as a consultant. Dr. Rudick has received personal compensation for activities with Biogen Idec, Genzyme, and Wyeth/Pfizer. Dr. Rudick has received research support from Biogen Idec through the Cleveland Clinic. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience.