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Stalevo

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Stalevo

Stalevo

CLINICAL PHARMACOLOGY

Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements.

Mechanism of Action

Levodopa

Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.

Carbidopa

When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for transport to the brain. When coadministered with levodopa, carbidopa increases plasma levels of levodopa and reduces the amount of levodopa required to produce a given response by about 75%. Carbidopa prolongs the plasma half-life of levodopa from 50 minutes to 1.5 hours and decreases plasma and urinary dopamine and its major metabolite, homovanillic acid. The Tmax of levodopa, however, was unaffected by the coadministration.

Entacapone

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).

In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

When entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and carbidopa alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease. The higher levodopa levels may also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.

When 200 mg entacapone is coadministered with levodopa/carbidopa, it increases levodopa plasma exposure (AUC) by 35%-40% and prolongs its elimination half-life in Parkinson's disease patients from 1.3 to 2.4 hours. Plasma levels of the major COMT-mediated dopamine metabolite, 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD), are also markedly decreased proportionally with increasing dose of entacapone.

In animals, while entacapone enters the CNS to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of entacapone on central COMT activity in humans have not been studied.

Pharmacokinetics

The pharmacokinetics of Stalevo® (carbidopa, levodopa and entacapone) tablets have been studied in healthy subjects (age 45-75 years old). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo (carbidopa, levodopa and entacapone) ® or as carbidopa/levodopa product plus Comtan® (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable.

Absorption/Distribution

Both levodopa and entacapone are rapidly absorbed and eliminated, and their distribution volume is moderately small. Carbidopa is absorbed and eliminated slightly more slowly compared with levodopa and entacapone. There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone, particularly concerning its Cmax.

The food-effect on the Stalevo (carbidopa, levodopa and entacapone) ® tablet has not been evaluated.

Levodopa

The pharmacokinetic properties of levodopa following the administration of single-dose Stalevo® (carbidopa, levodopa and entacapone) tablets are summarized in Table 1.

Table 1. Pharmacokinetic Characteristics of Levodopa With Different Tablet Strengths of Stalevo (carbidopa, levodopa and entacapone) ® (mean ± SD)

Tablet Strength AUC0-∞
(ng·h/mL)
Cmax
(ng/mL)
Tmax
(h)
12.5-50-200mg 1040 ±314 470 ±154 1.1 ±0.5
25-100-200mg 2910 ±715 975 ± 247 1.4 ±0.6
37.5 - 150- 200 mg 3770 ±1120 1270 ±329 1.5 ±0.9
50 - 200 - 200 mg 61 15 ±1536 1859 ±455 1.76 ±0.7

Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa (see PRECAUTIONS).

Levodopa is bound to plasma protein only to a minor extent (about 10%-30%).

Carbidopa

Following administration of Stalevo (carbidopa, levodopa and entacapone) ® as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 to 3.4 hours on average. The mean Cmax ranged from about 40 to 225 ng/mL and the mean AUC from 170 to 1200 ng•h/mL, with different Stalevo (carbidopa, levodopa and entacapone) ® strengths providing 12.5 mg, 25 mg, 37.5 mg or 50 mg of carbidopa.

Carbidopa is approximately 36% bound to plasma protein.

Entacapone

Following administration of Stalevo (carbidopa, levodopa and entacapone) ® as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 to 1.2 hours on average. The mean Cmax of entacapone was about 1200 to 1500 ng/mL and the AUC 1250 to 1750 ng•h/mL after administration of different Stalevo (carbidopa, levodopa and entacapone) ® strengths all providing 200 mg of entacapone.

The plasma protein binding of entacapone is 98% over the concentration range of 0.4-50 ng/mL. Entacapone binds mainly to serum albumin.

Metabolism and Elimination

Levodopa

The elimination half-life of levodopa, the active moiety of anti parkinsonian activity, was 1.7 hours (range 1.1-3.2 hours).

Levodopa is extensively metabolized to various metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).

Carbidopa

The elimination half-life of carbidopa was on average 1.6 to 2 hours (range 0.7-4.0 hours).

Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone

The elimination half-life of entacapone was on average 0.8 to 1 hour (0.3-4.5 hours).

Entacapone is almost completely metabolized prior to excretion with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, the only active metabolite. Entacapone and the cis-isomer are eliminated in the urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis-isomer glucuronides). The glucuronide conjugate of the cis-isomer is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces.

Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly.

Special Populations

Hepatic Impairment

Stalevo® (carbidopa, levodopa and entacapone)

While there are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment, Stalevo (carbidopa, levodopa and entacapone) ® should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone.

Entacapone

Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa/dopa decarboxylase inhibitor coadministration, showed approximately two-fold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Consequently, Stalevo (carbidopa, levodopa and entacapone) ® should be administered with care to patients with biliary obstruction or hepatic disease.

Renal Impairment

Stalevo® (carbidopa, levodopa and entacapone)

Stalevo (carbidopa, levodopa and entacapone) ® should be administered cautiously to patients with severe renal disease. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment.

Entacapone

No important effects of renal function on the pharmacokinetics of entacapone were found. The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa/dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance > 1.12 mL/sec/1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60-0.89 mL/sec/1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20-0.44 mL/sec/1.73 m2).

Concurrent Diseases

Stalevo (carbidopa, levodopa and entacapone) ® should be administered cautiously to patients with biliary obstruction, hepatic disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, or endocrine disease.

Elderly

Stalevo (carbidopa, levodopa and entacapone) ® tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years old. In the pharmacokinetics studies conducted in healthy volunteers following single dose of carbidopa/levodopa/entacapone (as Stalevo (carbidopa, levodopa and entacapone) ® or as separate carbidopa/levodopa and Comtan tablets):

Levodopa

The AUC of levodopa is significantly (on average 10%-20%) higher in elderly (60-75 years) than younger subjects (45-60 years). There is no significant difference in the Cmax of levodopa between younger (45-60 years) and elderly subjects (60-75 years).

Carbidopa

There is no significant difference in the Cmax and AUC of carbidopa, between younger (45-60 years) and elderly subjects (60-75 years).

Entacapone

The AUC of entacapone is significantly (on average, 15%) higher in elderly (60-75 years) than younger subjects (45-60 years). There is no significant difference in the Cmax of entacapone between younger (45-60 years) and elderly subjects (60-75 years).

Gender

The bioavailability of levodopa is significantly higher in females when given with or without carbidopa and/or entacapone. Following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo (carbidopa, levodopa and entacapone) ® or as separate carbidopa/levodopa and Comtan tablets in healthy volunteers (age range 45-74 years):

Levodopa

The plasma exposure (AUC and Cmax) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for Cmax). These differences are primarily explained by body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight.

Carbidopa

There is no gender difference in the pharmacokinetics of carbidopa.

Entacapone

There is no gender difference in the pharmacokinetics of entacapone.

Drug Interactions

See PRECAUTIONS: DRUG INTERACTIONS

Clinical Studies

Each Stalevo (carbidopa, levodopa and entacapone) ® tablet, provided in six single-dose strengths, contains carbidopa and levodopa in ratio 1:4 and a 200 mg dose of entacapone. Four Stalevo (carbidopa, levodopa and entacapone) ® tablet strengths 12.5/50/200 mg, 25/100/200 mg, 37.5/150/200 mg and 50/200/200 mg have been shown to be bioequivalent to the corresponding doses of standard-release carbidopa/levodopa 25/100 mg tablets and Comtan 200 mg tablets.

The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson's disease was established in three 24-week multicenter, randomized, double-blind placebo-controlled trials in patients with Parkinson's disease. In two of these trials, the patients' disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of these trials, patients were stabilized on levodopa for 2-4 weeks.

There is limited experience of using entacapone in patients who do not experience fluctuations.

In the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa-levodopa (up to 10 times daily, but averaging 4-6 doses per day). The formal double-blind portion of both trials was 6 months long. Patients recorded the time spent in the "On" and "Off states in home diaries periodically throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18-hour diary recorded day (6 a.m. to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state.

In addition to the primary outcome measure, the amount of time spent in the "Off state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V & VI); an investigator's and patient's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's disease; and the change in daily carbidopa-levodopa dose.

In one of the studies, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either carbidopa-levodopa or benserazide-levodopa). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa-levodopa.

The following tables display the results of these two trials:

Table 2. Nordic Study

Primary Measure from Home Diary (from an 18-hour Diary Day)
  Baseline Change from Baseline at Month 6* p-value vs. placebo
Hours of Awake Time "On"
  Placebo 9.2 +0.1 -
  Entacapone 9.3 +1.5 < 0.001
Duration of "On" Time After First AM Dose (Hrs)
  Placebo 2.2 0.0 -
  Entacapone 2.1 +0.2 < 0.05
Secondary Measures from Home Diary (from an 18-hour Diary Day)
Hours of Awake Time "Off"
  Placebo 5.3 0.0 -
  Entacapone 5.5 -1.3 < 0.001
Proportion of Awake Time "On" *** (%)
  Placebo 63.8 +0.6 -
  Entacapone 62.7 +9.3 < 0.001
Levodopa Total Daily Dose (mg)
  Placebo 705 +14 -
  Entacapone 701 -87 < 0.001
Frequency of Levodopa Daily Intakes
  Placebo 6.1 +0.1 -
  Entacapone 6.2 -0.4 < 0.001
Other Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
Investigator's Global (overall) % Improved**
  Placebo - 28 -
  Entacapone - 56 < 0.01
Patient's Global (overall) % Improved**
  Placebo   22  
  Entacapone - 39 N.S.
UPDRS Total
  Placebo 37.4 -1.1 -
  Entacapone 38.5 -4.8 < 0.01
UPDRS Motor
  Placebo 24.6 -0.7 -
  Entacapone 25.5 -3.3 < 0.05
UPDRS ADL
  Placebo 11.0 -0.4 -
  Entacapone 11.2 -1.8 < 0.05
* Mean; the month 6 values represent the average of weeks 8,16, and 24, by protocol-defined outcome measure.
** At least one category change at endpoint.
*** Not an endpoint for this study but primary endpoint in the North American Study.
Not significant.

Table 3. North American Study

Primary Measure from Home Diary (for a 24-hour Diary Day)
  Baseline Change from Baseline at Month 6* p-value vs. placebo
Percent of Awake Time "On"
  Placebo 60.8 +2.0 -
  Entacapone 60.0 +6.7 < 0.05
Secondary Measures from Home Diary (for a 24-hour Diary Day)
Hours of Awake Time "Off"
  Placebo 6.6 -0.3 -
  Entacapone 6.8 -1.2 < 0.01
Hours of Awake Time "On"
  Placebo 10.3 + 0.4  
  Entacapone 10.2 + 1.0 N.S.
Levodopa Total Daily Dose (mg)
  Placebo 758 + 19 -
  Entacapone 804 -93 < 0.001
Frequency of Levodopa Daily Intakes
  Placebo 6.0 + 0.2  
  Entacapone 6.2 0.0 N.S.
Other Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
Investigator's Global (overall) % Improved**
  Placebo - 21 -
  Entacapone - 34 < 0.05
Patient's Global (overall) % Improved**
  Placebo - 20 -
  Entacapone - 31 < 0.05
UPDRS Total***
  Placebo 35.6 +2.8 -
  Entacapone 35.1 -0.6 < 0.05
UPDRS Motor***
  Placebo 22.6 +1.2 -
  Entacapone 22.0 -0.9 < 0.05
UPDRS ADL***
  Placebo 11.7 +1.1 -
  Entacapone 11.9 0.0 < 0.05
* Mean; the month 6 values represent the average of weeks 8,16, and 24, by protocol-defined outcome measure.
** At least one category change at endpoint.
*** Score change at endpoint similarly to the Nordic Study.
Not significant.

Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.

Withdrawal of entacapone

In the North American study, abrupt withdrawal of entacapone, without alteration of the dose of carbidopa-levodopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within two weeks following levodopa dose increase on average by 80 mg. In the Nordic study, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg.

In the third placebo-controlled trial, a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other two trials, entacapone 200 mg was administered with each dose of levodopa/dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily "On" time were the primary measures of effectiveness. The following results were seen for the primary measures, as well as for some secondary measures:

Table 4. German-Austrian Study

Primary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo (LOCF)
UPDRS ADL*
  Placebo 12.0 +0.5 -
  Entacapone 12.4 -0.4 < 0.05
UPDRS Motor*
  Placebo 24.1 +0.1 -
  Entacapone 24.9 -2.5 < 0.05
Hours of Awake Time "On" (Home Diary)**
  Placebo 10.1 +0.5  
  Entacapone 10.2 +1.1 N.S.
Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
UPDRS Total*
  Placebo 37.7 +0.6 -
  Entacapone 39.0 -3.4 < 0.05
Percent of Awake Time "On" (Home Diary)**
  Placebo 59.8 +3.5 _
  Entacapone 62.0 +6.5 N.S.
Hours of Awake Time "Off" (Home Diary)**
  Placebo 6.8 -0.6 -
  Entacapone 6.3 -1.2 0.07
Levodopa Total Daily Dose (mg)*
  Placebo 572 +4 -
  Entacapone 566 -35 N.S.
Frequency of Levodopa Daily Intake*
  Placebo 5.6 +0.2 -
  Entacapone 5.4 0.0 < 0.01
Global (overall) % Improved***
  Placebo _ 34 _
  Entacapone - 38 N.S.
* Total population; score change at endpoint.
** Fluctuating population, with 5-10 doses; score change at endpoint.
*** Total population; at least one category change at endpoint.
Not significant.

Last reviewed on RxList: 11/8/2010
This monograph has been modified to include the generic and brand name in many instances.

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