Stalevo is an anti-parkinsonian
dopaminergicDopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
combination medication that contains
carbidopaCarbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
, levodopa, and
entacaponeEntacapone is a drug that functions as a catechol-O-methyl transferase inhibitor. It is used in the treatment of Parkinson's disease....
for the treatment of
Parkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
. It is marketed by Swiss-based
NovartisNovartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
Pharmaceuticals and manufactured by Finnish drugmaker
Orion CorporationOrion Corporation, founded in 1917 and headquartered at Espoo, Finland, is a Finnish company, which develops, manufactures and markets pharmaceuticals, active pharmaceutical ingredients and diagnostic tests for global markets...
.
Indications
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
dyskinesiaDyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
s.
Extension
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).
Dosing forms
Stalevo is supplied as tablets in six strengths:
catechol-O-methyltransferase (COMT) inhibitorA COMT inhibitor is a drug that inhibits the action of catechol-O-methyl transferase. This enzyme is involved in degrading neurotransmitters. COMT inhibitors are used in the treatment of Parkinson's disease....
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.
Side effects
It is important to take Stalevo at regular intervals according to the schedule outlined by a doctor. Sometimes a weaning 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.
Drug interactions
Stalevo is contraindicated in patients taking a class of antidepressant drugsAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
known as non-selective monoamine oxidase (MAO) inhibitorsMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
such as phenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
and tranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
. 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 rasagilineRasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
or selegilineSelegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
. 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 EmsamEmsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
, 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.
Studies
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
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 cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
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.
FIRST-STEP
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.
Prostate cancer
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 cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
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 screeningProstate cancer screening is an attempt to identify individuals with prostate cancer in a broad segment of the population—those for whom there is no reason to suspect prostate cancer. There are two methods used: One is the digital rectal examination , in which the examiner inserts a gloved,...
. 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.
Cardiovascular risks
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.
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