|Carbidopa||Dopa decarboxylase inhibitor|
|Pregnancy cat.||C (US)|
|Legal status||℞-only (US)|
|(what is this?)|
Stalevo is an anti-parkinsonian dopaminergic combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease. It is marketed by Swiss-based Novartis Pharmaceuticals and manufactured by Finnish drugmaker Orion Corporation.
- 1 Indications
- 2 Dosing forms
- 3 Dosing
- 4 Mechanism of action
- 5 Side effects
- 6 Drug interactions
- 7 Studies
- 8 Safety
- 9 See also
- 10 References
- 11 External links
Stalevo was approved by the FDA in June 2003 to treat adult patients with idiopathic Parkinson’s disease in two scenarios. First, to substitute with equivalent strength of each of the three components for immediate-release carbidopa/levodopa and entacapone previously administered as individual products. Second, to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" but only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias.
As of 2010[update] Applications for extending the indication of Stalevo to patients requiring initiation of levodopa therapy have been under review by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA), based on the favourable results from FIRST-STEP, a study conducted in North America and Europe by Novartis from 2005 to 2007 (see below).
Stalevo is supplied as tablets in six strengths:
Parkinson's disease, idiopathic
Maximum 1 tablet per dose, 8 tablets per day (all but the highest strength tablets), 6 tablets per day (Stalevo 200). Tablets are not to be cut, crushed, or chewed.
Not defined. In severe impairment caution is advised.
Not defined. In severe impairment caution is advised.
Pediatric dosing is currently unavailable and/or not applicable.
Mechanism of action
Levodopa is the immediate precursor to dopamine. Entacapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor that increases the bioavailability of levodopa. Entacapone does not cross the blood–brain barrier. Carbidopa is a peripheral aromatic L-amino acid decarboxylase (AADC) inhibitor. Carbidopa, which also does not cross the blood–brain barrier, is combined with levodopa to prevent its conversion to dopamine in the periphery.
It is important to take Stalevo at regular intervals according to the schedule outlined by a doctor. Sometimes a wearing off effect may occur at the end of the dosing interval, where a patient may feel Parkinson's symptoms. Urine, saliva, or sweat may be discolored (dark color such as red, brown, or black) after taking Stalevo.
Stalevo is contraindicated in patients taking a class of antidepressant drugs known as non-selective monoamine oxidase (MAO) inhibitors such as phenelzine and tranylcypromine. Combining Stalevo with these drugs could cause serious—possibly life-threatening—side effects. MAO inhibitors should be stopped at least two weeks before starting therapy with Stalevo.
Stalevo may be combined with the drugs rasagiline or selegiline. These drugs are a different type of MAO inhibitor known as selective MAO inhibitors that are often prescribed for Parkinson's disease. Many drug interactions involving selegiline are theoretical, primarily based on interactions with non-selective MAO inhibitors; at oral doses the risk of these interactions may be very low. However, transdermal selegiline, known by its trade name Emsam, is still contraindicated. Transdermal selegiline results in higher plasma levels at which it behaves like a non-selective MAO inhibitor. Concominant use of entacapone, a component of Stalevo, with MAO inhibitors may increase toxicity of MAO inhibitors. Levodopa, also a component of Stalevo, in combination with MAO inhibitors may result in hypertensive reactions.
The supporting literature provided with Stalevo notes several studies undertaken to determine the various properties and clinical effectiveness of carbidopa, levodopa, and entacapone in non-combination form. Two studies, STRIDE-PD and FIRST-STEP, have been undertaken specifically to evaluate Stalevo.
STRIDE-PD (Stalevo Reduction in Dyskinesia Evaluation), is the first long-term clinical trial evaluating Stalevo in Parkinson's disease. It sought to demonstrate a delay in the onset of motor complications such as dyskinesias in patients taking Stalevo compared to those taking a traditional levodopa/carbidopa medication. The study is an international, multi-center, randomized, double-blind, parallel group, active-controlled study. The study was conducted between September 2004 and November 2008 in 77 centers and 14 countries, including 31 sites in the United States, Canada and the following European countries: Austria, Belgium, France, Finland, Germany, Greece, Italy, Spain, Sweden, Turkey, Switzerland, United Kingdom. A total of 745 patients enrolled in the trial and 541 completed treatment. Of the patients who completed treatment, 265 patients received Stalevo and 276 received carbidopa/levodopa. Treatment lasted between 2.6 years and 4 years (mean duration: 2.7 years). The average age of patients in the trial was approximately 60 years. The majority of subjects were Caucasian (95.2%) and male (62.7%). The study was aimed to provide support for extending the current EU indication to early Parkinson's disease.
In February 2009, the result of the primary endpoint measured in STRIDE-PD demonstrated that Stalevo does not delay the onset of involuntary movements, dyskinesia. Therefore the primary objective of STRIDE-PD study was not achieved.
Prostate cancer data
A total of 467 men received randomized treatment in the trial. Among those who received treatment, there was a higher number of cases of prostate cancer in patients in the Stalevo group compared those in the carbidopa/levodopa group. Specifically, 9 out of 245 males (3.7%, 95% Confidence Interval: 1.69% - 6.86%) had prostate cancer in the Stalevo group compared to the 2 out of 222 males (0.9%) in the carbidopa/levodopa group. The incidence rate of prostate cancer was 14 cases/1,000 patient years for Stalevo and 3.2 cases/1,000 patient years for carbidopa/levodopa. The odds ratio for the occurrence of prostate cancer in males taking Stalevo was 4.19 (95% Confidence Interval: 0.90– 19.63). Duration of therapy prior to diagnosis of prostate cancer in the Stalevo-treated group ranged from 148 days to 949 days (mean: 664 days).
Previous clinical trials with Stalevo did not find an increased risk for prostate cancer. Most of these trials evaluating this drug were conducted for less than a year, whereas STRIDE-PD was conducted over a 4-year period, with a mean duration of exposure of 2.7 years.
The FIRST-STEP (Favorability of Immediate-Release carbidopa/levodopa vs STalevo; Short-Term comparison in Early Parkinson's) study was a double-blind, randomized, parallel group, fixed-dose, clinical trial that included 423 patients with early Parkinson's disease in eight countries. It was sponsored by Novartis and conducted in the USA, Canada and six other countries between 2005 and 2007. The patients were randomized to receive three daily doses of either Stalevo or levodopa/carbidopa, each containing 100 mg of the active drug, levodopa. Each patient received treatment for 9 months. The primary end-point of the study was the change from baseline in combined UPDRS (Unified Parkinson's Disease Rating Scale) part II and III scores measuring activities of daily living and motor function in patients with PD. The treatment difference was statistically significant (p<0.05) in favour of Stalevo. The conclusion was that Stalevo provides better symptomatic benefit than standard levodopa/carbidopa treatment in early Parkinson's Disease.
On March 31, 2010, the United States Food and Drug Administration stated it is evaluating long-term clinical data from STRIDE-PD which found that a greater number of patients taking Stalevo had prostate cancer compared to those taking carbidopa/levodopa. 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 were advised to be aware of this possible risk and follow current guidelines for prostate cancer screening. FDA recommended that healthcare professionals follow the recommendations in the drug label when prescribing Stalevo and Comtan. Patients were directed to not stop taking their medication unless directed to do so by their healthcare professional.
On August 20, 2010, the United States Food and Drug Administration stated meta-analysis of several studies "appeared to show an increase in the risk of heart attack, stroke, and cardiovascular death for people taking the drug" but also stated "findings were not clear." Heart problems are not uncommon in Parkinson's patients and the FDA will investigate the concerns.
- Drug Reference for FDA Approved Parkinson's Disease Drugs Retrieved 2010-4-1
- Orion: Primary objective of STRIDE-PD study was not achieved Retrieved 2010-3-31
- Novartis Stalevo Insert Retrieved 2010-4-1
- Stalevo Adult Dosing - ePocrates Online Retrieved 2010-4-2
- Stalevo Pediatric Dosing - ePocrates Online Retrieved 2010-4-2
- Stalevo patient advice including side effects - Drugs.com Retrieved 2010-4-2
- Stalevo Drug Interactions - ePocrates Online Retrieved 2010-4-2
- Leikin, Jerrold B. & Paloucek, Frank P. (2007). Poisoning and toxicology handbook (4th ed.). Informa Health Care. p. 610. ISBN 1-4200-4479-6. Google Book Search. Retrieved on April 2, 2010.
- STRIDE-PD Study Information Retrieved 2010-3-31
- FDA Drug Safety Communication: Ongoing Safety Review of Stalevo (entacapone/carbidopa/levodopa) and possible development of Prostate Cancer Retrieved 2010-4-2
- Patients with early Parkinson's disease experienced better symptomcontrol and improvements in daily activities with Stalevo thancarbidopa/levodopa, according to newly-published study Retrieved 31-3-2010
- Positive Primary Endpoint from FIRST-STEP Study with Stalevo in Early Parkinson's Disease Retrieved 31-3-2010
- FDA evaluating cancer link in Parkinson's drug Retrieved 2010-3-31
- Stalevo (entacapone/carbidopa/levodopa): Ongoing Safety Review Retrieved on 2010-4-2
- FDA to review heart risks of Parkinson's drug Retrieved 2010-8-20