Levodopa Entacapone

Oral sustained-release (Sinemet CR) 25 mg carbidopa and 100 mg levodopa 50 mg carbidopa and 200 mg levodopa Carbidopa/levodopa/entacapone (Stalevo)... 

CARBIDOPA/LEVODOPA/ENTACAPONE (Stalevo 50 tablets 12.5 mg carbidopa, 50 mg levodopa, 200 mg entacapone)... 

Solla, R, A. Cannas, F. Marrosu et al. Therapeutic interventions and adjustments in the management of Parkinson disease Role of combined carbidopa/levodopa/entacapone (Stalevo). 6, 2010 483-90. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

Parkinson s disease As an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson s disease who experience the signs and symptoms of end-of-dose wearing-off. The effectiveness of entacapone has not been systematically evaluated in patients with idiopathic Parkinson s disease who do not experience end-of-dose wearing-off. ... 

The recommended dose of entacapone is one 200 mg tablet administered concomitantly with each levodopa/carbidopa dose to a maximum of 8 times/day (200 mg X 8 = 1600 mg/day). Clinical experience with daily doses greater than 1600 mg is limited. 

Always administer entacapone in combination with levodopa/carbidopa. Entacapone has no antiparkinsonian effect of its own. 

In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been 800 mg or more, or if they had moderate or severe dyskinesias prior to treatment with entacapone. 

Entacapone can be combined with the immediate- and sustained-release formulations of levodopa/carbidopa. 

Pharmacology Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which alters the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (such as carbidopa), plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. 

Hypotension/Syncope Dopaminergic therapy in patients with Parkinson s disease has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. However, in entacapone clinical trials, no differences from placebo were seen for measured orthostasis or symptoms of orthostasis. 

Hallucinations Dopaminergic therapy in Parkinson s disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4% of patients treated with 200 mg entacapone or placebo. Dyskinesia Entacapone may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. 

Use carbidopa, levodopa, and entacapone combination as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. Some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with carbidopa, levodopa, and entacapone combination if a decision has been made to add entacapone. 

The optimum daily dosage of carbidopa, levodopa, and entacapone combination must be determined by careful titration in each patient. Carbidopa, levodopa, and entacapone combination tablets are available in 3 strengths, each in a 1 4 ratio of carbidopa to levodopa and combined with 200 mg of entacapone in a standard... 

Clinical experience with daily doses above 1600 mg of entacapone is limited. It is recommended that no more than 1 carbidopa, levodopa, and entacapone combination tablet be taken at each dosing administration. Thus, the maximum recommended daily dose of carbidopa, levodopa, and entacapone combination is 8 tablets/day. 

Transferring patients currently treated with carbidopa/levodopa and entacapone to carbidopa, levodopa, and entacapone combination tablet ... 

Carbidopa/levodopa - There is no experience in transferring patients currently treated with formulation of carbidopa/levodopa other than immediate release carbidopa/levodopa with a 1 4 ratio (controlled release formulations, or standard release presentations with a 1 10 ratio of carbidopa/levodopa) and entacapone to carbidopa, levodopa, and entacapone combination. 

Entacapone - Patients who are currently treated with entacapone 200 mg tablet with each dose of standard release carbidopa/levodopa, can be directly switched to the corresponding strength of carbidopa, levodopa, and entacapone combination containing the same amounts of levodopa and carbidopa. 

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa by decreasing the strength of carbidopa, levodopa, and entacapone combination at each administration or by decreasing the frequency of administration by extending the time between doses. 

When more levodopa is required, take the next higher strength of carbidopa, levodopa, and entacapone combination and/or increase the frequency of doses, up to a maximum of 8 times daily and not to exceed the maximum daily dose recommendations as outlined above. 

Addition of other antiparkinsonian medications Standard drugs for Parkinson disease may be used concomitantly while carbidopa, levodopa, and entacapone... 

Entacapone and tolcapon are selective and reversible catechol-O-methyltransferase (COMT) inhibitors which also inhibit the break down of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone fComtan). They are used in combination with levodopa-carbidopa. In patients with motor fluctuations, they increase the on time. Adverse effects are similar to those observed with levodopa-carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver enzymes for signs of hepatic changes. 

Take entacapone with carbidopa and levodopa for best results... 

Geriatric Considerations - Summary Entacapone inhibits peripheral COMT and increases levodopa s effects. Itsprimary role is as adjunctive therapy to prolong the beneficial effects of levodopa and to decrease end-of-dose fluctuations in response to treatment. Concurrent use of levodopa is necessary for entacapone to be effective and unlike tolcapone, hepatic monitoring is not required. 

Kieburtz K, et al. Entacapone improves motor fluctuations in levodopa-treated Parkinson s disease patients. Ann Neurol 1997,52 747-755. 

Rine UK, Larsen IP, Siden A, et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology i 998,51 278-285. 

Modeling is an analytical tool that can be used to extrapolate shorter term clinical results, such as days of improved symptoms in Parkinson s disease patients in a study over 6 months, to longer time periods. A model was developed to extrapolate the results of a 6-month trial in which patients received either levodopa alone or levodopa plus the catechol-o-methyltransferase (COMT) inhibitor entacapone. Comtan (entacapone) is designed to reduce the metabolism of levodopa in peripheral tissue and vessels so that more of the drug is available in the brain at a more constant rate than is seen with levodopa alone. The 6-month clinical trial produced clinical results that allow us to establish entacapone s effect on the OFF time associated with levodopa therapy. OFF time refers to a re-emergence of symptoms prior to the next scheduled levodopa dose. Entacapone reduces the OFF time and increases the ON time of levodopa therapy. 

Figure 9.2 illustrates the various inputs and outputs of a model built to demonstrate the 5-year results of therapy with entacapone (Comtan1 ), which represents a novel pharmacological principle used in combination with levodopa therapy. The inputs list the data fed into the model. The clinical effects of the therapy are taken from the clinical trials. The costs by disease stage are defined as costs for >25% OFF time per day (severe stage) and costs for <25% OFF time per day (less severe) and are taken from literature sources. Patient preference data (used to calculate QALYs) for these two disease stages are taken from a separate study of patient preferences. The outputs of the model list some of the more common uses of the model ... 

Presented in Fig. 9.3 is an example of a model used to extrapolate the 6-month trial results of a COMT inhibitor (entacapone) used in combination with levodopa versus levodopa alone in the treatment of Parkinson s disease. This particular model is an example of a Markov model... 

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