STALEVO - carbidopa, levodopa and entacapone tablet, film coated
Novartis Pharmaceuticals Corporation
----------
Stalevo® 50
Stalevo® 75
Stalevo® 100
Stalevo® 125
Stalevo® 150
Stalevo® 200
(carbidopa, levodopa and entacapone) Tablets
Rx only
Prescribing Information
DESCRIPTION
Stalevo® (carbidopa, levodopa and entacapone) is a combination of carbidopa, levodopa and entacapone for the treatment of Parkinson's disease.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4•H2O, and its structural formula is
Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is
Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N3O5 and its structural formula is
Stalevo® (carbidopa, levodopa and entacapone) is supplied as tablets in six strengths: Stalevo® 50, containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone; Stalevo® 75, containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone; Stalevo® 100, containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone; Stalevo® 125, containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone; Stalevo® 150, containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone; Stalevo® 200, containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone.
The inactive ingredients of the Stalevo® tablet are corn starch, croscarmellose sodium, glycerol 85%, hypromellose, magnesium stearate, mannitol, polysorbate 80, povidone, sucrose, red iron oxide, and titanium dioxide. Stalevo® 50, Stalevo® 100, and Stalevo® 150 also contain yellow iron oxide.
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® 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® tablet has not been eva luated.
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® (mean ± SD)
|
Tablet Strength |
AUC0-∞
(ng∙h/mL) |
Cmax
(ng/mL) |
Tmax
(h) |
|
12.5 - 50 - 200 mg |
1040 ± 314 |
470 ± 154 |
1.1 ± 0.5 |
|
25 - 100 - 200 mg |
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 |
6115 ± 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® 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® 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 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® strengths all providing 200 mg of entacapone.
The plasma protein binding of entacapone is 98% over the concentration range of 0.4-50 µg/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 1.1-3.2 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® 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® should be administered with care to patients with biliary obstruction or hepatic disease.
Renal Impairment
Stalevo® (carbidopa, levodopa and entacapone)
Stalevo® 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® should be administered cautiously to patients with biliary obstruction, hepatic disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, or endocrine disease.
Elderly
Stalevo® 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® 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® 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® tablet, provided in six single-dose strengths, contains carbidopa and levodopa in ratio 1:4 and a 200 mg dose of entacapone. Four Stalevo® 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 eva luated, and patients were also eva luated 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 |
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 |
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:
