Stalevo 125 FDA Alerts
The FDA Alerts below may be specifically about Stalevo 125 or relate to a group or class of drugs which include Stalevo 125.
MedWatch Safety Alerts are distributed by the FDA and published by Drugs.com. Following is a list of possible medication recalls, market withdrawals, alerts and warnings.
Recent FDA Alerts for Stalevo 125
FDA Review Finds No Increased Risk of Prostate Cancer with Parkinson's Disease Medicines Containing Entacapone (Comtan, Stalevo)
August 13, 2019 -- A U.S. Food and Drug Administration (FDA) review of additional data found no increased risk of prostate cancer with the use of entacapone to treat Parkinson’s disease. We conducted this review after an earlier trial1 suggested this possible risk. As a result, our recommendations for using Comtan (entacapone) and Stalevo (a combination of entacapone, carbidopa, and levodopa) will remain the same in the prescribing information.
We alerted the public in March 2010 that we were aware of a clinical trial1 suggesting a possible increased risk of prostate cancer with the entacapone component of Stalevo. We subsequently required the Stalevo manufacturer, Novartis, to conduct a study2 to further evaluate this potential risk. We also studied this issue independently using data from the Department of Veterans Affairs health care system.3 Based on these additional studies, we concluded that entacapone use is not associated with an increased risk of prostate cancer (see Data Summary).
Medicines that contain entacapone with carbidopa and levodopa have been shown to effectively treat symptoms of Parkinson’s disease such as muscle stiffness, tremors, spasms, and poor muscle control. These medicines have been approved and on the market for almost 20 years. The combination of entacapone with carbidopa and levodopa in Stalevo has been shown to reduce end-of-dose “wearing-off” in patients with Parkinson’s disease to a greater degree than with entacapone alone or with the two-drug combination of carbidopa and levodopa.
Health care professionals should follow standard prostate cancer screening recommendations for patients.
Patient and caregivers should continue to take your medicine as prescribed. Talk to your health care professionals if you have any questions or concerns.
To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving entacapone-containing products or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
Data Summary
An unexpected finding in the Stalevo Reduction in Dyskinesia Evaluation – Parkinson's Disease (STRIDE-PD) trial was that a greater number of patients taking Stalevo were observed to have prostate cancer compared to those taking carbidopa/levodopa.1 STRIDE-PD evaluated the time to onset of dyskinesia, or difficulty controlling voluntary movement, in patients with Parkinson's disease taking Stalevo compared to those taking only carbidopa/levodopa. To further assess this safety concern, in 2011 we required the manufacturer of Stalevo, Novartis, to conduct an observational cohort study in patients with Parkinson’s disease, comparing the incidence rate of prostate cancer in a cohort of patients treated with entacapone plus a conventional PD treatment of dopa decarboxylase inhibitor/levodopa (DDCI/LD) with a cohort of patients treated with DDCI/LD plus either a dopamine agonist or a monoamine oxidase B inhibitor
The study involved 11,396 men in Finland with Parkinson’s disease, 1,141 of whom received entacapone. A total of 359 prostate cancer cases occurred during an average follow-up time of 4.6 years, with 89 prostate cancer deaths during an average follow-up time of 4.7 years. Treatment with DDCI/LD with add-on entacapone (Group 1) was not associated with an increased risk of prostate cancer (hazard ratio [HR]=1.05; 95% confidence interval [CI]=0.76-1.44) or prostate cancer mortality (HR=0.93; 95% CI: 0.43-1.98) compared to treatment with DCCI/LD without add-on entacapone (Group 2). Similarly, evaluation of the secondary objectives showed that longer cumulative treatment with entacapone was not associated with an increased risk of prostate cancer or prostate cancer death. The HR estimates for patients with more than 360 days cumulative treatment with entacapone were 0.82 (95% CI: 0.56-1.18) for prostate cancer incidence and 1.27 (95% CI: 0.59-2.72) for prostate cancer death, respectively, compared to patients with no entacapone treatment.
Table 1. Risks of Prostate Cancer (PC) Development and Mortality – Results from Finnish Study
| Outcome+ | Adj Hazard Ratio | 95% Confidence Interval | |
|---|---|---|---|
| Group 1: Group 2 | PC incidence | 1.05 | 0.76-1.44 |
| Group 1: Group 2 | PC mortality | 0.93 | 0.43-1.98 |
| Cumulative treatment >360 days | PC incidence | 0.82 | 0.56-1.18 |
| Cumulative treatment >360 days | PC mortality | 1.27 | 0.60-2.72 |
*Exposure to conventional PD treatment of dopa decarboxylase inhibitor/levodopa (DCCI/LD) with or without add-on entacapone
The study had limitations in the design and how the results were analyzed. The main limitations included the short period of time that Stalevo had been available in Finland compared to the long latency period of prostate cancer, the potential for decreased surveillance for prostate cancer in male patients with advanced Parkinson’s disease, and lack of information pertaining to important factors such as family history of prostate cancer and prior screenings for prostate cancer.
The FDA and Veterans Affairs (VA) Center for Medication Safety also conducted a retrospective cohort study3 of 17,666 U.S. male veterans with Parkinson’s disease treated with levodopa-carbidopa (n=5,257), comparing add-on entacapone therapy to the control cohort, which received add-on therapy with a dopamine agonist or monoamine oxidase B inhibitor (n=12,409). Patients were followed for occurrence of prostate cancer using data from the VA cancer registry. Mean follow-up time was 3.1 years and 4.0 years, respectively, in the entacapone and control cohorts. Twenty-three prostate cancer cases occurred in the entacapone cohort and 97 in the control cohort. There was no difference in risk of prostate cancer between the cohorts for increased duration of cumulative entacapone treatment of more than 2 years (adjusted HR=1.08; 95% CI: 0.46-2.51). Time since starting drug therapy and cumulative dose also did not suggest a difference in prostate cancer risk between the cohorts.
The low overall incidence rate of 1.8 cases of prostate cancer per 1,000 person-years compared to the age-adjusted rate of 1.3 per 1,000 U.S. males in the general population may reflect a possible bias in cancer ascertainment after Parkinson’s disease was diagnosed. This may be partly due to a decrease in screening for prostate cancer in the U.S., particularly in men with chronic medical conditions. This may have led to a potential decrease in prostate cancer detection, a limitation of the study.
References
- Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang AE, Olanow CW. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 2010 Jul; 68(1):18-27.
- Korhonen P, Haukka J, Kuoppamaki M, Ellmen J, Aho V, Vahteristo M. The risk of developing prostate cancer in entacapone and levodopa/DDCI users compared to levodopa/DDCI users without entacapone – A nation-wide retrospective register-based study. EPID Research Oy, Tekniikantie, Finland. June 25, 2013.
- Major JM, Dong D, Cunningham F, et al. Entacapone and prostate cancer in Parkinson’s disease patients: A large Veterans Affairs healthcare system study. Parkinsonism and Relat Disord 2018 Aug;53:46-52.
Source: FDA
Entacapone: Drug Safety Communication - FDA Review Found No Increased Cardiovascular Risks
Including Comtan (entacapone) and Stalevo (entacapone, carbidopa, and levodopa)
ISSUE: An FDA safety review has found no clear evidence of an increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson’s disease. As a result, recommendations for using Comtan (entacapone) and Stalevo (a combination of entacapone, carbidopa, and levodopa) will remain the same in the drug labels.
FDA alerted patients and health care professionals about a possible increased risk for cardiovascular events and death with Stalevo in August 2010. This possible safety issue was observed in a clinical trial called the Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s Disease (STRIDE-PD) and in a meta-analysis that combined the cardiovascular-related findings from 15 clinical trials comparing Stalevo to carbidopa/levodopa. Carbidopa and levodopa have been used extensively and have not been shown to have an increased cardiovascular risk. FDA was concerned that the entacapone in Stalevo was responsible for these cardiovascular risks because the comparison drugs do not contain this ingredient.
To better understand the significance of these findings, FDA required the Stalevo manufacturer, Novartis, to study the potential for cardiovascular risk with the entacapone component of the drug. FDA examined the results from this required study and from one additional study and concluded they do not show an increased risk of cardiovascular adverse events with entacapone. The results observed in the original meta-analysis were driven by results of a single study (STRIDE-PD), which was not designed to assess cardiovascular risks. FDA believes that the meta-analysis and STRIDE-PD results are chance findings and do not represent a true increase in risk due to entacapone.
BACKGROUND: Entacapone-containing products, Comtan and Stalevo, have been shown to be effective in treating symptoms of Parkinson’s disease, such as muscle stiffness, tremors, spasms, and poor muscle control. The combination of entacapone with carbidopa and levodopa in Stalevo has been shown to reduce end-of-dose “wearing-off” in patients with Parkinson’s disease to a greater degree than with entacapone alone or with the two-drug combination of carbidopa and levodopa.
RECOMMENDATION: Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:
- Complete and submit the report Online: www.accessdata.fda.gov/scripts/medwatch/index.cfm
- Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
[10/26/2015 - Drug Safety Communication - FDA]
Stalevo(carbidopa/levodopa and entacapone): Ongoing Safety Review: Possible increased cardiovascular risk
Issue: FDA notified healthcare professionals that it is evaluating clinical trial data that suggest patients taking Stalevo (a combination of carbidopa/levodopa and entacapone) may be at an increased risk for cardiovascular events (heart attack, stroke, and cardiovascular death) compared to those taking carbidopa/levodopa (sold as the combination product, Sinemet). FDA's decision to conduct a meta-analysis was based on findings from the Stalevo Reduction In Dyskinesia Evaluation – Parkinson's Disease or STRIDE-PD trial, which reported an imbalance in the number of myocardial infarctions in patients treated with Stalevo compared to those receiving only carbidopa/levodopa. Although myocardial infarction, cardiac irregularities, hypertension, and palpitations have been reported with levodopa, previous clinical trials with Stalevo did not show an imbalance in myocardial infarction, stroke, and cardiovascular death.
Background: Both Stalevo and Sinemet have been shown to be effective treatments for the symptoms of Parkinson's disease. The addition of entacapone to carbidopa/levodopa has been shown to lead to a greater degree of improvement in some of the symptoms of Parkinson's disease than treatment with carbidopa/levodopa alone. Entacapone is also available as a single ingredient product (sold under the brand name Comtan) to be always administered in association with carbidopa/levodopa (entacapone has no antiparkinsonian effect of its own). It is estimated that 154,000 patients were dispensed a prescription for Stalevo from its approval in June 2003 through October 2009.
Recommendations: At this time, FDA's review of the potential cardiovascular risk with Stalevo is ongoing. Healthcare professionals should regularly evaluate the cardiovascular status of patients who are taking Stalevo, especially if they have a history of cardiovascular disease. Patients should not stop taking Stalevo unless told to do so by their healthcare professional.
FDA is exploring additional ways to assess whether Stalevo increases the risk of cardiovascular events, and will update the public when this review is complete.
[08/20/2010 - Drug Safety Communication - FDA]
Related MedWatch Safety Alert, March 2010
Stalevo (entacapone/carbidopa/levodopa): Ongoing Safety Review
FDA notified healthcare professionals and patients that it is evaluating data from a long-term clinical trial called Stalevo Reduction in Dyskinesia Evaluation - Parkinson's Disease (STRIDE-PD), that may suggest that patients taking Stalevo may be at an increased risk for developing prostate cancer. Other controlled clinical trials evaluating Stalevo or Comtan (entacapone) did not find an increased risk of prostate cancer. FDA is still reviewing the available information and has not concluded that Stalevo increases the risk of developing prostate cancer. Healthcare professionals should be aware of this possible risk and follow current guidelines for prostate cancer screening. FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing Stalevo and Comtan. Patients should not stop taking their medication unless directed to do so by their healthcare professional.
[03/31/2010- Drug Safety Communication - FDA]
