Background: Antiparkinsonian pharmacotherapy represents one of the most important expenses related to Parkinson’s disease. The application of generic drugs may help to reduce the economic burden of the disease; however, efficacy and safety of these products have been less studied. Objective: To investigate the efficacy and safety of generic rasagiline (Ralago<sup>®</sup>) from a clinical perspective. Methods: The Clinical Global Impression of Severity scale was used to rate the most important motor and non-motor symptoms at baseline and 12 weeks after the initiation of Ralago<sup>®</sup>. Patients also identified symptoms which were the main sources of their disability and distress in everyday life. Results: A total of 499 patients were enrolled (231 females, mean age: 73.2 ± 9.1 years, mean duration of disease: 3.6 ± 3.7 years). Of them, 486 patients completed the study protocol. Both motor and non-motor symptoms showed improvement during 12-week Ralago<sup>®</sup> treatment. Adverse events were rare, and the majority of them were not considered as serious. Conclusions: The generic rasagiline (Ralago<sup>®</sup>) is an effective and safe generic product.
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by a broad spectrum of both motor and non-motor symptoms (NMS) which can dramatically impair health-related quality of life (HRQoL) [
MAO-B inhibitors are widely used agents improving the metabolism of both endogenous and exogenous dopamine and producing symptomatic benefits [
The economic impact of PD largely results from the direct expenses related to antiparkinsonian pharmacotherapy. Antiparkinsonian medications are not considered to be the most expensive pharmacological agents; however, the long treatment duration and the frequently applied complex drug combinations [
Commercially available original and generic antiparkinsonian drugs are considered to be pharmaceutically equivalent or pharmaceutical alternatives if they meet the same or comparable standards [
Generic drugs may also be pharmaceutical alternatives, medicinal products with the same active substance but in different salts or esters. In the European Union, several pharmaceutical alternatives exist, for example, amantadine-sulfate (PK-MERZ®), and amantadine-chlorate (e.g. Viregyt®). The majority of the generic products for rasagiline are also pharmaceutical alternatives containing rasagiline-tartrate instead of rasagiline-mesylate used in the branded counterpart.
Postmarketing studies on generic drugs are warranted, especially if they contain pharmacological alternative ingredients. Therefore, an open-label, multicenter, non-invasive, observational 12-week clinical trial was conducted on the effects of a generic antiparkinsonian drug containing rasagiline (Ralago®, Krka, Slovenia).
The KPASES 04/2016-RALAGO/HU study of motor and non-motor symptoms in patients with Parkinson’s disease after 12-week treatment with irreversible MAO-B inhibitor Ralago® (rasagiline) was performed in Hungary. The study protocol was approved by the National Institute of Pharmacy and Nutrition (OGYÉI/1382-4/2017).
The active ingredient of the investigated product is rasagiline-tartrate. In addition to 1 mg of this active substance, the durg contains some additives including cellulose microcrytals, maize strach, silicon dioxid, talc, and stearic acid.
With the participation of 40 Hungarian movement disorders centers, those patients were enrolled in this study who presented at the included centers between March 2017 and October 2017 and fulfilled the following inclusion criteria: 1) patient was at least 18 years old at baseline; 2) diagnosis of PD in accordance with the UK Brain Bank criteria could be established; 3) patient had Hoehn Yahr stage II or III PD; 4) Ralago® 1 mg per day treatment was initiated, in monotherapy or in combination with other antiparkinsonian drugs, independently of this study; and 5) written consent according to the approval of the National Institute of Pharmacy and Nutrition was signed. Treatment with other MAO inhibitors, including OTC drugs, or pethidine; known hypersensitivity to rasagiline or any additive of the product; severe hepatic damage; and pregnancy or nursing were exclusion criteria. Originally, the enrollment of 500 patients with PD was planned, however, a total of 499 was achieved within the planned timeframe.
At baseline (Visit 1), demographic, medication, and disease-related data were recorded. The severity of motor and non-motor symptoms, including bradykinesia, rigidity, tremor, postural instability, daytime sleepiness, fatigue, mood disturbances, psychosis, memory disturbances, social difficulties, sexual dysfunction, urinary problems, olfactory disturbances, and pain, were rated by clinicians using the Clinical Global Impression of Severity (CGI-S) scale (0 = normal; 1 = mild; 2 = moderate; 3 = severe, and 4 = very severe) [
12 weeks after the initiation of Ralago® treatment (Visit 2), clinicians reevaluated both the motor and NMS of the disease. Data of patients underwent both the baseline and the 12-week follow-up examinations were used for the evaluation of antiparkinsonian efficacy of Ralago®. The safety profile of the product was evaluated based on data of all enrolled patients.
Although the study was sponsored by Krka (Slovenia), the pharmaceutical company producing Ralago®, data analysis was completely independent of the sponsor. The IBM SPSS software package (version 24.0., IBM Inc, Armonk, NY, USA) was used for statistical analysis. Because the variables did not follow the normal distribution, Wilcoxon’s signed rank test was used during comparison of the two visits. The level of statistical significance was set at 0.05.
A total of 499 patients were enrolled with computable data for Visit 1 (231 females, mean age at baseline: 73.2 ± 9.1 years, mean disease duration at baseline: 3.6 ± 3.7 years). Demographic-, medication-, and disease-related data of patients at Visit 1 are shown in
Most of the patients (89.7%) were between 60 and 90 years of age. Numbers of enrolled males (53.7%) and females (46.3%) were roughly equal. Nearly all the subjects (99.6%) were Caucasian. Two-thirds of the patients had a 1 to 5-year history of PD, and 17.4% of them suffered from motor fluctuations at baseline. 100 patients (20.0%) received no specific antiparkinsonian medication at the enrollment. Comparing medication data at Visit 1 and Visit 2, the initiation of Ralago® led to a slight reduction in the application of other antiparkinsonian drugs in the study population. Medication data of patients at Visit 2 are represented in
Safety data analysis was performed on the whole population (study population, n = 499); whereas, the efficacy calculations were based on the data of 486 patients who underwent both the Visit 1 and the Visit 2 (efficacy population). Data of thirteen patients could not be inlcuded in efficacy analysis because of
Mean ± SD or count (%) | |||
---|---|---|---|
Age (years) | 73.2 ± 9.1 | ||
40 - 49 | 8 (1.6%) | ||
50 - 59 | 35 (7.0%) | ||
60 - 69 | 107 (21.4%) | ||
70 - 79 | 226 (45.3%) | ||
80 - 89 | 115 (23.0%) | ||
90 - 99 | 8 (1.6%) | ||
Sex | |||
Male | 268 (53.7%) | ||
Female | 231 (46.3%) | ||
Race | |||
Caucasian | 497 (99.6%) | ||
Asian | 1 (0.2%) | ||
Other | 1 (0.2%) | ||
Disease duration (years) | 3.6 ± 3.7 | ||
<1 | 60 (12.0%) | ||
1 - 5 | 332 (66.5%) | ||
6 - 10 | 82 (16.4%) | ||
11 - 15 | 17 (3.4%) | ||
16 - 20 | 6 (1.2%) | ||
20 - 25 | 2 (0.4%) | ||
Presence of motor fluctuations at baseline | |||
No | 412 (82.6%) | ||
Yes | 87 (17.4%) | ||
Antiparkinsonian treatment at baseline | |||
No | 100 (20.0%) | ||
Yes | 399 (80.0%) | ||
L-dopa + benserazide | 144 (28.9%) | ||
LCE | 75 (15.0%) | ||
Ropinirole | 74 (14.8%) | ||
Pramipexole | 67 (13.4%) | ||
Rotigotine | 46 (9.2%) | ||
Selegiline | 56 (11.2%) | ||
Amantadine | 37 (7.4%) | ||
Procyclidine | 1 (0.2%) | ||
Biperiden | 4 (0.8%) | ||
Other | 42 (8.4%) | ||
Abbreviations: SD = standard deviation; LCE = L-dopa + carbidopa + entacapone.
unacceptable level of missing values and/or study termination prior to Visit 2.
According to CGI-S ratings, Ralago® significantly improved all the cardinal motor symptoms of PD, including tremor, bradykinesia, and rigidity; moreover, it also had beneficial effects on postural instability. Besides, a significant reduction was found in the severity of all examined NMS—with the exception of psychosis—after 12 weeks of Ralago® treatment (
Count (%) | |
---|---|
L-dopa + benserazide | 135 (27.1%) |
L-dopa + carbidopa + entacapone | 72 (14.4%) |
Ropinirole | 63 (12.6%) |
Pramipexole | 58 (11.6%) |
Rotigotine | 47 (9.4%) |
Selegiline | 8 (1.6%) |
Rasagiline | 470 (94.2%) |
Amantadine | 40 (8.0%) |
Procyclidine | 1 (0.2%) |
Biperiden | 3 (0.6%) |
Other | 3 (0.6%) |
CGI-S scores at baseline (Visit 1) | CGI-S scores at 12-week follow-up (Visit 2) | p-values | |
---|---|---|---|
Bradykinesia | 2.2 ± 1.2 | 1.6 ± 1.1 | <0.001 |
Rigidity | 1.8 ± 1.0 | 1.3 ± 0.9 | <0.001 |
Tremor | 2.0 ± 1.3 | 1.3 ± 1.1 | <0.001 |
Postural instability | 1.5 ± 1.4 | 1.1 ± 1.3 | <0.001 |
Daytime sleepiness | 1.9 ± 1.5 | 1.6 ± 1.4 | <0.001 |
Fatigue | 2.7 ± 1.4 | 2.2 ± 1.3 | <0.001 |
Mood disturbances | 2.0 ± 1.5 | 1.6 ± 1.4 | <0.001 |
Psychosis | 0.2 ± 0.6 | 0.2 ± 0.7 | 0.950 |
Memory disturbances | 2.7 ± 1.5 | 1.5 ± 1.4 | 0.001 |
Social difficulties | 2.8 ± 1.6 | 1.4 ± 1.5 | <0.001 |
Sexual dysfunction | 1.0 ± 1.5 | 0.9 ± 1.3 | 0.006 |
Urinary problems | 1.5 ± 1.5 | 1.4 ± 1.5 | 0.024 |
Olfactory disturbances | 3.9 ± 1.7 | 4.0 ± 1.6 | 0.001 |
Pain | 1.1 ± 1.7 | 1.0 ± 1.5 | <0.001 |
Data are shown as mean ± standard deviation. Lower scores represent better state. Abbreviations: CGI-S = ClinicalGobal Impression of Severity.
The number of patients experiencing any changes is demonstrated in
Half of the included patients (50.4%) reported fatigue among the three most disabling symptoms in everyday life, followed by bradykinesia (48.6%) and tremor (48.3%). The same symptoms were most frequently reported among the three main sources of distress in daily living. Psychosis, olfactory disturbances and sexual problems were most rarely responsible for disability and distress in everyday life (
A total of 37 AEs were reported in 31 patients. Of them, six AEs were serious (persistent incapacity due to lumbar vertebral fracture in one case and death in five cases). Based on the judgment of the physician, these events were not associated with the use of Ralago®. The main underlying cause of death could be the high mean age of the study cohort (cardiovascular and cerebrovascular events, n = 5). The most common non-serious AEs were gastrointestinal disturbances, including stomachache, meteorism, and abdominal spasms; worsening of tremor; sleep disturbances; dizziness; urinary problems such as incontinence and strangury; and agitation or hallucinations. Of the non-serious AEs, 19 events were considered to be in association with Ralago® treatment, and most of them completely disappeared after the discontinuation of the drug (
Symptoms | Number and percent of patients | |||
---|---|---|---|---|
with improvement | with no change | with worsening | p-values* | |
Bradykinesia | 226 (46.7%) | 242 (50.0%) | 16 (3.3%) | <0.001 |
Rigidity | 186 (38.4%) | 279 (57.6%) | 19 (3.9%) | <0.001 |
Tremor | 243 (50.3%) | 221 (45.8%) | 19 (3.9%) | <0.001 |
Postural instability | 161 (33.3%) | 302 (62.5%) | 20 (4.1%) | <0.001 |
Daytime sleepiness | 137 (28.3%) | 290 (59.9%) | 57 (11.8%) | <0.001 |
Fatigue | 212 (43.9%) | 229 (47.4%) | 42 (8.7%) | <0.001 |
Mood disturbances | 148 (30.6%) | 287 (59.3%) | 49 (10.1%) | <0.001 |
Psychosis | 21 (4.4%) | 442 (91.7%) | 19 (3.9%) | <0.001 |
Memory disturbances | 92 (19.2%) | 338 (70.4%) | 50 (10.4%) | <0.001 |
Social difficulties | 120 (26.8%) | 298 (66.5%) | 30 (6.7%) | <0.001 |
Sexual dysfunction | 55 (11.5%) | 397 (82.7%) | 28 (5.8%) | <0.001 |
Urinary problems | 69 (14.5%) | 365 (76.8%) | 41 (8.6%) | <0.001 |
Olfactory disturbances | 41 (8.5%) | 423 (88.1%) | 16 (3.3%) | <0.001 |
Pain | 137 (28.4%) | 306 (63.5%) | 39 (8.1%) | <0.001 |
*Chi-square test was utilized to calculate p-values. Abbreviations: CGI-S = ClinicalGobal Impression of Severity.
The most disabling symptom | The main source of distress | ||
---|---|---|---|
Fatigue | 244 (50.4%) | Fatigue | 229 (47.3%) |
Bradykinesia | 235 (48.6%) | Tremor | 209 (43.2%) |
Tremor | 234 (48.3%) | Bradykinesia | 199 (41.1%) |
Postural instability | 143 (29.5%) | Pain | 156 (32.2%) |
Pain | 120 (24.8%) | Postural instability | 126 (26.0%) |
Mood disturbances | 108 (22.3%) | Mood disturbances | 116 (24.0%) |
Daytime sleepiness | 87 (18.0%) | Memory disturbances | 92 (19.0%) |
Memory disturbances | 85 (17.6%) | Daytime sleepiness | 80 (16.5%) |
Rigidity | 76 (15.7%) | Urinary problems | 71 (14.7%) |
Urinary problems | 46 (9.5%) | Rigidity | 67 (13.8%) |
Social difficulties | 34 (7.0%) | Social difficulties | 51 (10.5%) |
Sexual dysfunction | 9 (1.9%) | Sexual dysfunction | 15 (3.1%) |
Olfactory disturbances | 7 (1.4%) | Olfactory disturbances | 10 (2.1%) |
Psychosis | 6 (1.2%) | Psychosis | 9 (1.9%) |
Data are count (%) and cumulative frequencies are represented.
To the best of our knowledge, this is the first study evaluating the efficacy and safety of a generic rasagiline formulation from a clinical perspective. Our multicenter observational postmarketing examination demonstrated that Ralago® is effective and safe as a monotherapy or as adjunctive therapy to other antiparkinsonian medications.
To date, only a few clinical trials have addressed the question of efficacy and safety of generic antiparkinsonian drugs. A possible reason for this can be that current regulations of licensing a new generic drug require only the demonstration of bioequivalence with the commercially available branded originator. However, this approach may not translate into clinical efficacy and safety [
In a long-term open-label study, Pahwa et al. found that conversion of Sinemet® to generic carbidopa/levodopa did not affect efficacious symptomatic control in the majority of PD patients (69%). However, the switch led to a deterioration in the clinical status of patients with marked motor fluctuations and dose failures. Therefore, it was suggested that generic drugs may not be eligible for treatment of a subgroup of PD patients [
Frequency | Duration* and outcome | Drug discontinued | Relation to drug | ||
---|---|---|---|---|---|
Serious adverse events | |||||
Death | 5 | Unrelated in all cases | |||
Lumbar vertebral fracture | 1 | Persistent incapacity | NO | Unrelated | |
Non-serious adverse events | |||||
Gastrointestinal problems** | 4 | Transient with full recovery | YES | Related | |
Transient with full recovery | YES | Related | |||
Transient with full recovery | YES | Related | |||
Persistent with improvement | Transient discontinuation | Unrelated | |||
Hallucinations | 4 | Transient with full recovery | Decrease of dose | Related | |
Persistent with improvement | Transient discontinuation | Unrelated | |||
Persistent with improvement | Transient discontinuation | Unrelated | |||
Persistent with no change | YES | Related | |||
Worsening of tremor | 3 | Transient with full recovery | YES | Related | |
Persistent with no change | Decrease of dose | Related | |||
Persistent with worsening | Transient discontinuation | Unrelated | |||
Sleep problems | 2 | Transient with full recovery | NO | Unrelated | |
Unknown | NO | Unknown | |||
Dizziness | 2 | Transient with full recovery | YES | Related | |
Persistent with improvement | YES | Related | |||
Urinary problems*** | 2 | Transient with full recovery | YES | Related | |
Transient with full recovery | YES | Related | |||
Excitement | 2 | Persistent with no change | YES | Related | |
persistent with worsening | Transient discontinuation | Unrelated | |||
Facial edema | 1 | Transient with full recovery | YES | Related | |
Nightmares | 1 | Transient with full recovery | YES | Related | |
Neck pain | 1 | Transient with full recovery | YES | Unrelated | |
Headache | 1 | Persistent with no change | Decrease of dose | Related | |
Gait impairment and fall | 1 | Transient with full recovery | NO | Unrelated | |
Sensation of suboccipital tension | 1 | Transient with full recovery | YES | Related | |
Weakness | 1 | Persistent with improvement | YES | Unrelated | |
Nervousness and agressivity | 1 | Transient with full recovery | Transient discontinuation | Related | |
Confusion | 1 | Persistent with improvement | YES | Unrelated | |
Discontinuation of the drug by the patient | 1 | Persistent with no change | YES | Unrelated | |
Not specified | 2 | Persistent with improvement | Transient discontinuation | Related | |
Unknown | Unknown | Unknown |
*Transient adverse events were completelyresolved within the study period; **Gastrointestinal problems include stomach ache, meteorismand abdominal spasms; ***Urinary problems include incontinence and strangury.
Similarly, the results of our present study also support the efficacy and safety of generic rasagiline, Ralago®. It seems to have beneficial effects on the control of both the early cardinal motor symptoms of PD and other disabling motor features emerging in later stages of the disease, such as postural instability. Furthermore, Ralago® also appears to own the previously described ability of rasagiline to beneficially influence the severity of NMS in PD [
The safety profile of the product can also be considered very good. Adverse events were rare (n = 37), and most of them were considered as non-serious. The half of all adverse events—including all the serious adverse events (n = 6)—were not in association with Ralago® treatment. Adverse events related to the drug completely disappeared after withdrawal. Comparing the results of safety analysis of this study to those of other clinical trials investigating other rasagiline-containing products [
The strength of this study lies in the high number of enrolled PD patients and the longitudinal study design. However, one of the most important limitations is the lack of utilization of a well-established PD-specific rating scale (e.g., MDS-UPDRS). Because of the time constraints in the majority of the examination sites, the CGI-S was chosen as the main outcome measure. It is a valid and reliable tool for assessing severity of symptoms [
To conclude, Ralago® was efficiently used as a monotherapy or as adjunctive therapy to other antiparkinsonian medications to improve symptomatic control in the Hungarian population suffering from PD. Beside its efficacy, Ralago® also had a very good safety profile which makes the product highly eligible for the safe pharmacotherapy of PD subjects being often elderly patients. As Ralago® seems to be able to improve a broad spectrum of disabling symptoms of PD, it may also have beneficial effects on HRQoL. Based on the results of the present study, Ralago® can be considered as a clinically useful generic product in the pharmacotherapy of PD.
Because the Ethical Approval of the present study does not authorize the authors and contributors to publish the data, they are not made available.
The study was sponsored by Krka (Slovenia). NK and DP were also supported by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002), NKFIH EFOP-3.6.2-16-2017-00008, NKFIH SNN125143, and ÚNKP-17-4-I.-PTE-311 government-based funds. Our research was partly financed by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the 5th thematic program of the University of Pécs, Hungary (20765/3/2018/FEKUSTRAT).
DP reported no financial disclosure.
JL received <1000 EUR consultation fees from Hungarian subsidiaries of Krka and Abbvie. Regarding this study the author did not receive any corporate funding.
JJ received <1000 EUR consultation fees from Hungarian subsidiaries of UCB, Valeant and Gerot. Regarding this study the author did not receive any corporate funding.
NK received <1000 EUR consultation fees from Hungarian subsidiaries of Medtronic, Boehringer Ingelheim, Novartis, GlaxoSmithKline, UCB, Krka and Abbvie. Regarding this study the author did not receive any corporate funding.
The authors declare no conflicts of interest regarding the publication of this paper.
The study investigators and centers were the following:
Pintér, D., Lajtos, J., Janszky, J. and Kovács, N. (2019) Clinical Experience with Generic Rasagiline (Ralago®) in Patients with Parkinson’s Disease: An Open-Label, Multicenter, Observational Study. Advances in Parkinson’s Disease, 8, 18-34. https://doi.org/10.4236/apd.2019.82003
AEs = adverse events; CGI-S = Clinical Global Impression of Severity; DA = dopamine agonists; MAO = monoamine oxidase; NMS = non-motor symptoms; PD = Parkinson’s disease
1. Research project: A. Conception, B. Organization, C. Execution;
2. Statistical Analysis: A. Design, B. Execution,
C. Review and Critique;
3. Manuscript: A. Writing of the first draft, B. Review and Critique
DP 1, 2, 3
JL 1, 2, 3
JJ 1A, 2C, 3B
NK 1, 2, 3