June 25, 2016
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Stalevo

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Stalevo




CLINICAL PHARMACOLOGY

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 because it does not cross the blood-brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood-brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the 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 delivery to the brain.

Entacapone

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

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. 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).

Pharmacokinetics

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

Absorption and 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 tablet has not been evaluated. Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa [see PATIENT INFORMATION].

Levodopa

The pharmacokinetic properties of levodopa following the administration of single-dose Stalevo (carbidopa, levodopa and entacapone) tablets are summarized in Table 3.

Table 3: Pharmacokinetic Characteristics of Levodopa with Different Tablet Strengths of Stalevo (mean ± SD)

Tablet Strength AUC0-∞ (nanogram-h per mL) C max (nanogram per mL) Tmax (h)
12.5 mg per 50 mg per 200 mg 1,040 ± 314 470± 154 1.1 ± 0.5
25 mg per 100 mg per 200 mg 2,910± 715 975 ± 247 1.4 ± 0.6
37.5 mg per 150 mg per 200 mg 3,770 ± 1,120 1,270 ± 329 1.5 ± 0.9
50 mg per 200 mg per 200 mg 6,115 ± 1,536 1,859 ± 455 1.76 ± 0.7

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

Carbidopa

Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 hours to 3.4 hours on average. The mean Cmax ranged from about 40 nanogram per mL to 225 nanogram per mL and the mean AUC from 170 nanogram•h per mL to 1,200 nanogram•h per mL, with different Stalevo 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 as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 hour to 1.2 hours on average. The mean Cmax of entacapone was about 1,200 nanogram per mL to 1,500 nanogram per mL and the AUC 1,250 nanogram•h per mL to 1,750 nanagram•h per mL after administration of different Stalevo strengths all providing 200 mg of entacapone.

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

Metabolism and Elimination

Levodopa

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

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

Carbidopa

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

Carbidopa is metabolized to two main metabolites (&apha;-methyl-3-methoxy-4-hydroxyphenylpropionic acid and &apha;-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 hour to 1 hour (0.3 hour to 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.

Renal Impairment

Entacapone

The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose in subjects with normal, moderate, and severely impaired renal functions, without levodopa and dopa decarboxylase inhibitor coadministration. No significant effects of renal function on the pharmacokinetics of entacapone were found.

Levodopa and carbidopa

No studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment.

Hepatic Impairment

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 and dopa decarboxylase inhibitor coadministration, showed approximately 2-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. Stalevo should be administered with care to patients with biliary obstruction or hepatic disease.

Levodopa and Carbidopa

There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment.

Geriatric Use

In the pharmacokinetics studies conducted in healthy volunteers following a single dose of carbidopa-, levodopa- and entacapone (as Stalevo or as separate carbidopa/levodopa and Comtan tablets):

Levodopa

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

Carbidopa

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

Entacapone

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

Gender

Pharmacokinetics following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo or as separate carbidopa/levodopa and Comtan tablets in healthy volunteers (age range 45 years to 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 Metabolized by COMT

When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively.

Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration [see DRUG INTERACTIONS].

Drugs Metabolized via CYP2C9

Due to its affinity to CYP2C9 in vitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. In an interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values increased on average by 13% [see DRUG INTERACTIONS].

Hormone Levels

Of the ingredients in Stalevo, levodopa is known to depress prolactin secretion and increase growth hormone levels.

Clinical Studies

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 studies in patients with Parkinson's disease. In 2 of these studies (Studies 1 and 2), 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 studies, patients were stabilized on levodopa for 2 weeks to 4 weeks.

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

In Studies 1 and 2, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa/levodopa (up to 10 times daily, but patients averaged 4 doses to 6 doses per day). The double-blind portion of both studies was 6 months long. Patients periodically recorded the time spent in the “On” and “Off” states in home diaries 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 and 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 Study 1, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Study 1), all of whom received concomitant levodopa plus dopa decarboxylase inhibitor (either carbidopa/levodopa or benserazide/levodopa). In Study 2, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa/levodopa.

The following tables (Table 4 and Table 5) display the results of these two studies:

Table 4: Efficacy Results of Study 1

Primary Measure from Home Diary (from an18-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 less than 0.001
Duration of “On” Time After First AM Dose (Hrs)
Placebo 2.2 0.0 -
Entacapone 2.1 +0.2 less than 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 less than 0.001
Proportion of Awake Time “On”*** (%)
Placebo 63.8 +0.6 -
Entacapone 62.7 +9.3 less than 0.001
Levodopa Total Daily Dose (mg)
Placebo 705 +14 -
Entacapone 701 -87 less than 0.001
Frequency of Levodopa Daily Intakes
Placebo 6.1 +0.1 -
Entacapone 6.2 - 0.4 less than 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 less than 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 less than 0.01
UPDRS Motor
Placebo 24.6 -0.7 -
Entacapone 25.5 -3.3 less than 0.05
UPDRS ADL
Placebo 11.0 -0.4 -
Entacapone 11.2 -1.8 less than 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.
‡‡P values for Secondary Measures are nominal P values without any adjustment for multiplicity.

Table 5: Efficacy Results of Study 2

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 less than 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 less than 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 less than 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 less than 0.05
Patient’s Global (overall) % Improved**
Placebo - 20 -
Entacapone - 31 less than 0.05
UPDRS Total***
Placebo 35.6 +2.8 -
Entacapone 35.1 -0.6 less than 0.05
UPDRS Motor***
Placebo 22.6 +1.2 -
Entacapone 22.0 -0.9 less than 0.05
UPDRS ADL***
Placebo 11.7 +1.1 -
Entacapone 11.9 0.0 less than 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.
‡‡P values for Secondary Measures are nominal P values without any adjustment for multiplicity.

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 Study 2, 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 2 weeks following levodopa dose increase on average by 80 mg. In Study 1, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed 2 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 (Study 3), a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other 2 studies, entacapone 200 mg was administered with each dose of levodopa and 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. Results for the primary measures, as well as for some secondary measures are presented in Table 6.

Table 6: Efficacy Results of Study 3

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 less than 0.05
UPDRS Motor*
Placebo 24.1 +0.1 -
Entacapone 24.9 -2.5 less than 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 less than 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 less than 0.01
Global (overall) % Improved***
Placebo - 34 -
Entacapone - 38 N.S.‡
*Total population; score change at endpoint.
**Fluctuating population, with 5 doses to 10 doses; score change at endpoint.
***Total population; at least one category change at endpoint.
‡Not significant.
‡‡P values for Secondary Measures are nominal P values without any adjustment for multiplicity.

Last reviewed on RxList: 2/10/2016
This monograph has been modified to include the generic and brand name in many instances.

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