Entacapone
Entacapone Tablets
FULL PRESCRIBING INFORMATION: CONTENTS*
- ENTACAPONE DESCRIPTION
- CLINICAL PHARMACOLOGY
- INDICATIONS & USAGE
- ENTACAPONE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- Hypotension and Syncope
- Diarrhea and Colitis
- Hallucinations
- Dyskinesia
- Other Events Reported With Dopaminergic Therapy
- Renal Toxicity
- Hepatic Impairment
- Information for Patients
- Laboratory Tests
- Special Populations
- Drug Interactions
- Protein Binding
- Drugs Metabolized by Catechol-O-methyltransferase (COMT)
- Hormone levels
- Effect of Entacapone on the Metabolism of Other Drugs
- Carcinogenesis
- Mutagenesis
- Impairment of Fertility
- Pregnancy
- Nursing Women
- ENTACAPONE ADVERSE REACTIONS
- DRUG ABUSE AND DEPENDENCE
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FULL PRESCRIBING INFORMATION
ENTACAPONE DESCRIPTION
O141535
CLINICAL PHARMACOLOGY
Mechanism of Action
O
Pharmacodynamics
COMT Activity in Erythrocytes: Studies in healthy volunteers have shown that entacapone reversibly inhibits human erythrocyte catechol‑O‑methyltransferase (COMT) activity after oral administration. There was a linear correlation between entacapone dose and erythrocyte COMT inhibition, the maximum inhibition being 82% following an 800 mg single dose. With a 200 mg single dose of entacapone, maximum inhibition of erythrocyte COMT activity is on average 65% with a return to baseline level within 8 hours.
Effect on the Pharmacokinetics of Levodopa and its Metabolites
When 200 mg entacapone is administered together with levodopa and carbidopa, it increases the area under the curve (AUC) of levodopa by approximately 35% and the elimination half-life of levodopa is prolonged from 1.3 h to 2.4 h. In general, the average peak levodopa plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s Disease patients suggest that the maximal effect occurs with 200mg entacapone. Plasma levels of 3‑OMD are markedly and dose-dependently decreased by entacapone when given with levodopa and carbidopa.
Pharmacokinetics of Entacapone
Entacapone pharmacokinetics are linear over the dose range of 5 mg to 800 mg, and are independent of levodopa and carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 h to 0.7 h based on the ß-phase and 2.4 h based on the g -phase. The g ‑phase accounts for approximately 10% of the total AUC. The total body clearance after intravenous administration is 850 mL per min. After a single 200 mg dose of Entacapone Tablets, the Cmax is approximately 1.2 microgram per mL.
Absorption : Entacapone is rapidly absorbed, with a Tmax of approximately 1 hour. The absolute bioavailability following oral administration is 35%. Food does not affect the pharmacokinetics of entacapone.
Distribution: The volume of distribution of entacapone at steady state after intravenous injection is small (20 L). Entacapone does not distribute widely into tissues due to its high plasma protein binding. Based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 microgram per mL to 50 microgram per mL. Entacapone binds mainly to serum albumin.
Metabolism and Elimination : 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, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate 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.
Special Populations : Entacapone pharmacokinetics are independent of age. No formal gender studies have been conducted. Racial representation in clinical trials was largely limited to Caucasians (there were only 4 blacks in one US trial and no Asians in any of the clinical trials); no conclusions can therefore be reached about the effect of entacapone on groups other than Caucasian.
Hepatic Impairment : A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately twofold 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, entacapone should be administered with care to patients with biliary obstruction.
Renal Impairment : The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa and dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance greater than 1.12 mL per sec per 1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 mL per sec per 1.73 m2 to 0.89 mL per sec per 1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20 mL per sec per 1.73 m2 to 0.44 mL per sec per 1.73 m2). No important effects of renal function on the pharmacokinetics of entacapone were found.
Drug Interactions : See PRECAUTIONS, Drug Interactions.
Clinical Studies
The effectiveness of Entacapone Tablets 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 the trials, patients were stabilized on levodopa for 2 weeks to 4 weeks. Entacapone has not been systematically evaluated 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 levodopa and carbidopa (up to 10 times daily, but averaging 4 doses to 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 AM 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 levodopa and carbidopa 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 levodopa and carbidopa or levodopa and benserazide). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa and carbidopa.
|
Primary Measure from Home Diary (from an 18-hour Diary Day)
|
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| |
Baseline |
Change from Baseline at Month 6  |
p-value vs. placebo |
||
|
Hours of Awake Time “On”
|
|||||
| Placebo |
9.2 |
+0.1 |
- |
||
| Entacapone Tablets |
9.3 |
+1.5 |
less than 0.001 |
||
|
Duration of “On” time after first AM dose
(hrs)
|
|||||
| Placebo |
2.2 |
0.0 |
- |
||
| Entacapone Tablets |
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 Tablets |
5.5 |
- 1.3 |
less than 0.001 |
||
|
Proportion of Awake Time “On” |
|||||
| Placebo |
63.8 |
+0.6 |
- |
||
| Entacapone Tablets |
62.7 |
+9.3 |
less than 0.001 |
||
|
Levodopa Total Daily Dose (mg)
|
|||||
| Placebo |
705 |
+14 |
- |
||
| Entacapone Tablets |
701 |
- 87 |
less than 0.001 |
||
|
Frequency of Levodopa Daily Intakes
|
|||||
| Placebo |
6.1 |
+0.1 |
- |
||
| Entacapone Tablets |
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 Tablets |
- |
56 |
less than 0.01 |
||
|
Patient’s Global (overall) % Improved |
|||||
| Placebo |
- |
22 |
- |
||
| Entacapone Tablets |
- |
39 |
N.S. |
||
|
UPDRS Total
|
|||||
| Placebo |
37.4 |
-1.1 |
- |
||
| Entacapone Tablets |
38.5 |
-4.8 |
less than 0.01 |
||
|
UPDRS Motor
|
|||||
| Placebo |
24.6 |
-0.7 |
- |
||
| Entacapone Tablets |
25.5 |
-3.3 |
less than 0.05 |
||
|
UPDRS ADL
|
|||||
| Placebo |
11.0 |
-0.4 |
- |
||
| Entacapone Tablets |
11.2 |
-1.8 |
less than 0.05 |
||
|
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 Tablets |
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 Tablets |
6.8 |
- 1.2 |
less than 0.01 |
|
Hours of Awake Time “On”
|
|||
| Placebo |
10.3 |
+ 0.4 |
- |
| Entacapone Tablets |
10.2 |
+ 1.0 |
N.S |
|
Levodopa Total Daily Dose (mg)
|
|||
| Placebo |
758 |
+ 19 |
- |
| Entacapone Tablets |
804 |
- 93 |
less than 0.001 |
|
Frequency of Levodopa Daily Intakes
|
|||
| Placebo |
6.0 |
+ 0.2 |
- |
| Entacapone Tablets |
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 Tablets |
- |
34 |
less than 0.05 |
|
Patient’s Global (overall) % Improved |
|||
| Placebo |
- |
20 |
- |
| Entacapone Tablets |
- |
31 |
less than 0.05 |
|
UPDRS Total |
|||
| Placebo |
35.6 |
+2.8 |
- |
| Entacapone Tablets |
35.1 |
-0.6 |
less than 0.05 |
|
UPDRS Motor |
|||
| Placebo |
22.6 |
+1.2 |
- |
| Entacapone Tablets |
22.0 |
-0.9 |
less than 0.05 |
|
UPDRS ADL |
|||
| Placebo |
11.7 |
+1.1 |
- |
| Entacapone Tablets |
11.9 |
0.0 |
less than 0.05 |
Withdrawal of entacapone
|
Primary Measures
|
||||||
| |
Baseline |
Change from Baseline at Month 6 |
p-value vs. placebo (LOCF) |
|||
|
UPDRS ADL |
||||||
| Placebo |
12.0 |
+0.5 |
- |
|||
| Entacapone Tablets |
12.4 |
-0.4 |
less than 0.05 |
|||
|
UPDRS Motor |
||||||
| Placebo |
24.1 |
+0.1 |
- |
|||
| Entacapone Tablets |
24.9 |
-2.5 |
less than 0.05 |
|||
|
Hours of Awake Time “On” (Home diary) |
||||||
| Placebo |
10.1 |
+0.5 |
- |
|||
| Entacapone Tablets |
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 Tablets |
39.0 |
-3.4 |
less than 0.05 |
|||
|
Percent of Awake Time “On” (Home diary) |
||||||
| Placebo |
59.8 |
+3.5 |
- |
|||
| Entacapone Tablets |
62.0 |
+6.5 |
N.S. |
|||
|
Hours of Awake Time “Off” (Home diary) |
||||||
| Placebo |
6.8 |
-0.6 |
- |
|||
| Entacapone Tablets |
6.3 |
-1.2 |
0.07 |
|||
|
Levodopa Total Daily Dose (mg) |
||||||
| Placebo |
572 |
+4 |
– |
|||
| Entacapone Tablets |
566 |
-35 |
N.S. |
|||
|
Frequency of Levodopa Daily Intake |
||||||
| Placebo
|
5.6 |
+0.2 |
– |
|||
| Entacapone Tablets |
5.4 |
0.0 |
less than 0.01 |
|||
|
Global (overall) % Improved |
||||||
| Placebo
|
– |
34 |
– |
|||
| Entacapone Tablets |
– |
38 |
N.S. |
|||
INDICATIONS & USAGE
ENTACAPONE CONTRAINDICATIONS
Entacapone Tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
WARNINGS
Drugs Metabolized By Catechol-O-Methyltransferase (COMT)
PRECAUTIONS
Hypotension and Syncope
Diarrhea and Colitis
Hallucinations
Dopaminergic therapy in Parkinson’s Disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4.0% of patients treated with 200 mg Entacapone Tablets or placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg Entacapone Tablets and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg Entacapone Tablets and placebo groups, respectively.
Dyskinesia
Entacapone Tablets may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 1.5% and 0.8% for 200 mg Entacapone Tablets and placebo, respectively.
Other Events Reported With Dopaminergic Therapy
Rhabdomyolysis
Hyperpyrexia and Confusion
Fibrotic Complications
Melanoma:
any
Renal Toxicity
In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so.
Hepatic Impairment
Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls. (See CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone and DOSAGE AND ADMINISTRATION).
Information for Patients
Laboratory Tests
Entacapone is a chelator of iron. The impact of entacapone on the body’s iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical trials. In a controlled clinical study serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in rates of anemia or decreased hemoglobin levels.
Special Populations
Patients with hepatic impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION).
Drug Interactions
In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use.
Protein Binding
Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam.
Drugs Metabolized by Catechol-O-methyltransferase (COMT)
See WARNINGS.
Hormone levels
Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects.
Effect of Entacapone on the Metabolism of Other Drugs
Carcinogenesis
Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Rats were treated once daily by oral gavage with entacapone doses of 20 mg per kg, 90 mg per kg, or 400 mg per kg. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose of entacapone (MRDD = 1,600 mg). Mice were treated once daily by oral gavage with doses of 20 mg per kg, 100 mg per kg or 600 mg per kg of entacapone (0.05, 0.3, and 2 times the MRDD for humans on a mg per m2 basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving the lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of entacapone administered in combination with levodopa and carbidopa has not been evaluated.
Mutagenesis
Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma and thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).
Impairment of Fertility
Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg per kg per day (plasma AUCs 28 times those in humans receiving the MRDD). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg per kg per day of entacapone.
Pregnancy
Nursing Women
Pediatric Use
There is no identified potential use of entacapone in pediatric patients.
ENTACAPONE ADVERSE REACTIONS
Adverse Event Incidence in Controlled Clinical Studies
|
SYSTEM ORGAN CLASS |
|
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|
Preferred term |
Entacapone Tablets (n = 603) % of patients |
Placebo (n = 400) % of patients |
|
|
|
SKIN AND APPENDAGES DISORDERS |
|
|||
|
Sweating increased |
2 |
1 |
|
|
|
MUSCULOSKELETAL SYSTEM DISORDERS |
|
|||
|
Back pain |
2 |
1 |
|
|
|
CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS |
|
|||
|
Dyskinesia |
25 |
15 |
|
|
|
Hyperkinesia |
10 |
5 |
|
|
|
Hypokinesia |
9 |
8 |
|
|
|
Dizziness |
8 |
6 |
|
|
|
SPECIAL SENSES, OTHER DISORDERS |
|
|||
|
Taste perversion |
1 |
0 |
|
|
|
PSYCHIATRIC DISORDERS |
|
|||
|
Anxiety |
2 |
1 |
|
|
|
Somnolence |
2 |
0 |
|
|
|
Agitation |
1 |
0 |
|
|
|
GASTROINTESTINAL SYSTEM DISORDERS |
|
|||
|
Nausea |
14 |
8 |
|
|
|
Diarrhea |
10 |
4 |
|
|
|
Abdominal pain |
8 |
4 |
|
|
|
Constipation |
6 |
4 |
|
|
|
Vomiting |
4 |
1 |
|
|
|
Mouth dry |
3 |
0 |
|
|
|
Dyspepsia |
2 |
1 |
|
|
|
Flatulence |
2 |
0 |
|
|
|
Gastritis |
1 |
0 |
|
|
|
Gastrointestinal disorders nos |
1 |
0 |
|
|
|
RESPIRATORY SYSTEM DISORDERS |
|
|||
|
Dyspnea |
3 |
1 |
|
|
|
PLATELET, BLEEDING AND CLOTTING DISORDERS |
|
|||
|
Purpura |
2 |
1 |
||
|
URINARY SYSTEM DISORDERS |
||||
|
Urine discoloration |
10 |
0 |
||
|
BODY AS A WHOLE - GENERAL DISORDERS |
||||
|
Back pain Fatigue Asthenia |
4 6 2 |
2 4 1 |
||
|
RESISTANCE MECHANISM DISORDERS |
||||
|
Infection bacterial |
1 |
0 |
||
Effects of gender and age on adverse reactions
No differences were noted in the rate of adverse events attributable to entacapone by age or gender.
DRUG ABUSE AND DEPENDENCE
Entacapone is not a controlled substance. Animal studies to evaluate the drug abuse and potential dependence have not been conducted. Although clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.
OVERDOSAGE
Management of Overdose
Management of Entacapone Tablets overdose is symptomatic; there is no known antidote to Entacapone Tablets. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Entacapone Tablets are highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Entacapone Tablets by decreasing its absorption and reabsorption from the GI tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind.
DOSAGE & ADMINISTRATION
Patients With Impaired Hepatic Function:max
Withdrawing Patients from Entacapone Tablets:
HOW SUPPLIED
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
EntacaponeEntacapone TABLET, FILM COATED
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