Entacapone

305.29

305.29

4975G9NM6T

DTXSID5046439

C61746

Crystals from acetic acid + hydrochloric acid

N04BX02|N04BA03|N - Nervous system

2942000000

130

2.1

Solid

1.4±0.1 g/cm3

162-163 °C

526.6°C at 760 mmHg

272.3±30.1 °C

1.642

DMSO: soluble 20mg/mL, clear

-20°C Freezer

3.25 mm Hg at 25 deg C (est)

Henry's Law constant = 6.76X10-19 atm-cu m/mol at 25 °C (est)

pKa1 = 5.95 (primary phenol); pKa2 = 10.41 (secondary phenol) (est)|pKa approximately 4.5

III

3

UN 1986 3/PG 3

1

R10:Flammable. R20/21/22:Harmful by inhalation, in contact with skin and if swallowed . R37/38:Irritating to respiratory system and skin . R41:Risk of serious damage to eyes. R62:Possible risk of impaired fertility. R38:Irritating to the skin. R36/37/38:Ir

S26-S36-S39-S45-S36/37/39-S16

KM5250000

Xn,T,F

Stable under recommended storage conditions.

P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including entacapone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (33.33%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Skin protection: Handle with gloves.|Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: General industrial hygiene practice.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Side effect include increase the occurrence of orthostatic hypotension, severe rhabdomyolysis, dyskinesia, hallucinations, hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects including abdominal pain constipation diarrhea nausea|IDENTIFICATION AND USE: Entacopone, a selective and reversible inhibitor of catechol-O-methyl-transfersase (COMT) is used as an adjunct to levodopa and carbidopa to treat end-of-dose "wearing-off" in patients with Parkinson's disease. HUMAN EXPOSURE AND TOXICITY: The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression. Catechol-O-methyltransferase (COMT) inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols. Postmarketing reports also indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during entacapone treatment or after starting or increasing the dose of entacapone. Therefore, patients with a major psychotic disorder should ordinarily not be treated with entacapone because of the risk of exacerbating psychosis. Entacapone was clastogenic in cultured human lymphocytes in the presence of metabolic activation. ANIMAL STUDIES: Rats were treated for two years with entacapone at daily doses of 20, 90, or 400 mg/kg by oral gavage. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose. Reproduction studies have been performed in rats and rabbits at doses up to 1000 mg/kg/day and 300 mg/kg/day, respectively, of entacapone. Increased incidence of fetal variations was evident in litters from rats treated at the highest dose in the absence of overt maternal toxicity. Increased frequencies of abortion and late/total resorptions and decreased fetal weights were observed in litters of rabbits treated with maternotoxic doses of 100 mg/kg/day or greater. There was no evidence of teratogenicity in these studies. When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, and anophthalmia) was observed in litters of dams treated with doses of 160 mg/kg/day or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day to female rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairments in the offspring. Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg/kg/day. Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone. Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence 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).

Entacapone therapy has been associated with serum aminotransferase elevations (above 3 times the upper limit of normal) in only 0.3% to 0.5% of patients, which is similar or minimally higher than the rate in subjects receiving placebo. The elevations were usually transient and asymptomatic and rarely required dose adjustment. In preliminary clinical trials, there were no reports of clinically apparent serious liver injury with jaundice. Subsequently, isolated instances of hepatotoxicity have been reported to the sponsor, injury arising 2 to 6 weeks after starting entacapone with mild jaundice and cholestatic pattern of liver enzyme elevations, and rapid recovery on stopping. Immunoallergic and autoimmune features were not present. The clinical phenotype of injury and associated features have not been reported in any detail. Thus, entacapone may rarely cause clinically apparent liver injury, but it has not been associated with the severe hepatitis and acute liver failure that characterized cases of tolcapone induced liver injury.

As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin, and chloramphenicol).|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.|Potential pharmacokinetic interaction (decreased entacapone excretion) with drugs interfering with biliary excretion, glucuronidation, and intestinal beta-glucuronidase (e.g., cholestyramine, probenecid, some anti-infectives (e.g., ampicillin, chloramphenicol, erythromycin, rifampin)).|Potential pharmacologic interaction (inhibits catecholamine metabolism) with nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine). Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline).|For more Interactions (Complete) data for ENTACAPONE (13 total), please visit the HSDB record page.

Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis.

98% (bind to serum albumin)

Used as an adjunct to levodopa / carbidopa in the symptomatic treatment of patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose "wearing-off".|FDA Label|Entacapone is indicated as an adjunct to standard preparations of levodopa / benserazide or levodopa / carbidopa for use in adult patients with Parkinson's disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations.|Entacapone is indicated as an adjunct to standard preparations of levodopa / benserazide or levodopa / carbidopa for use in patients with Parkinson's disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations.|Levodopa/Carbidopa/Entacapone Orion is indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa / dopa-decarboxylase (DDC)-inhibitor treatment.|Stalevo is indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa / dopa-decarboxylase (DDC)-inhibitor treatment.|Corbilta is indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.,

Entacapone is a catechol-O-methyltransferase inhibitor used in the therapy of Parkinson disease as adjunctive therapy in combination with levodopa and carbidopa. Entacapone has been associated with a low rate of serum enzyme elevations during treatment, but has yet to be implicated in cases of clinically apparent acute liver injury with jaundice.

Parkinson Disease Agents

Antiparkinson Agents; Enzyme Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health(NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Entacapone is included in the database.|Comtan is indicated as an adjunct to levodopa and carbidopa to treat end-of-dose "wearing-off" in patients with Parkinson's disease. /Included in US product label/|Stalevo, a combination drug consisting of levodopa, carbidopa (dopa decarboxylase inhibitor), and entacapone (catechol-O-methyltransferase-COMT inhibitor) is indicated for the treatment of Parkinson's disease. Stalevo can be used: to substitute (with equivalent strengths of each of the three components) carbidopa/levodopa and entacapone previously administered as individual products. To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias. /Included in US product label/|Parkinson's disease (PD) is a neurodegenerative disorder characterized by a variety of motor symptoms including freezing of gait (FOG), in which walking is transiently halted as if the patient's feet were 'glued to the ground'. Treatment of FOG is still challenging. Although L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline, has been on the market in Japan because of its beneficial effect for FOG, clinical use of L-DOPS has been far from satisfying. However, the fact that there were some responders to L-DOPS encouraged us to hypothesize that the enhancement of L-DOPS concentration in the brain by the co-administration of L-DOPS and a catechol-O-methyl transferase (COMT) inhibitor, which is expected to interrupt L-DOPS metabolism in the peripheral circulation, would be beneficial for FOG. Based on our hypothesis, we conducted a preliminary study with a small number of participants with FOG. Of the 16 PD patients with FOG who completed this study, group 1 (n=6) received L-DOPS co-administered with entacapone, which is a COMT inhibitor used worldwide as an anti-parkinson drug, group 2 (n=5) received entacapone alone, and group 3 (n=5) received L-DOPS alone. Only the patients in group 1 showed a significant improvement in FOG. Moreover, the beneficial effect was observed only in patients with levodopa-resistant FOG. This result supports our hypothesis, at least in patients with levodopa-resistant FOG, and shows that the co-administration of L-DOPS and entacapone could be a new strategy for FOG treatment.

Diarrhea was reported in 10% of patients receiving entacapone in clinical studies, and about 2% of patients required discontinuance of the drug because of diarrhea. Diarrhea generally was of mild to moderate intensity, but severe diarrhea, which required hospitalization, may occur rarely. Diarrhea generally occurs during the first 4-12 weeks of entacapone therapy, but may occur as early as the first week or as late as several months following initiation of entacapone therapy. Diarrhea generally resolved following discontinuance of the drug.|Findings from an FDA-conducted meta-analysis suggest that patients receiving combined therapy with levodopa, carbidopa, and entacapone may be at increased risk of cardiovascular events (i.e., myocardial infarction, stroke, cardiovascular death) compared with those receiving levodopa-carbidopa. The meta-analysis combined cardiovascular-related findings from 15 clinical trials that compared the combination of levodopa, carbidopa, and entacapone with levodopa-carbidopa and found a small but statistically significant increase in the risk of cardiovascular events in those receiving the levodopa, carbidopa, and entacapone regimen (relative risk: 2.46). However, the increased risk was driven largely by data from a single trial (STRIDE-PD); when this trial was removed from the analysis, the results were no longer significant. Various factors make it difficult to draw firm conclusions from this meta-analysis. Many of the trials included in the analysis had a duration of less than 6 months (possibly not long enough to detect cardiovascular risk) and were not specifically designed to evaluate cardiovascular safety. In addition, the majority of patients had preexisting cardiovascular risk factors. At this time, FDA has not concluded that combined therapy with levodopa, carbidopa, and entacapone is associated with an increased risk of cardiovascular events and is continuing to review the available data related to this safety concern. Patients currently receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) should continue to take the drugs as prescribed unless otherwise instructed by a clinician. Cardiac function should be monitored regularly in such patients, particularly in those with a history of cardiovascular disease.|Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In controlled studies, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension.|Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Comtan treatment or after starting or increasing the dose of Comtan. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of Comtan. Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Comtan.|For more Drug Warnings (Complete) data for ENTACAPONE (22 total), please visit the HSDB record page.

Entacapone is structurally and pharmacologically related to tolcapone, but unlike tolcapone, is not associated with hepatotoxicity. Entacapone is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. Entacapone selectively and reversiblly inhibits 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 the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and 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. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)|Compounds and drugs that inhibit or block the activity of CATECHOL O-METHYLTRANSFERASE enzymes. Drugs in this class are used in management of central nervous system disorders such as PARKINSON DISEASE. (See all compounds classified as Catechol O-Methyltransferase Inhibitors.)

Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.|Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. 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.|20 L|850 mL/min|In rats and in humans, the absolute bioavailability was dose-dependent and ranged from 20% to 55%, following single dose of 10, 65 and 400 mg/kg, in rats and from 29% to 49%, following single dose of 5, 25, 50, 100, 200, 400 and 800 mg, in humans.|Absorption of unchanged entacapone after single oral administration is quite rapid both in rats and in dogs. Two peaks in plasma concentrations, occurring at 5-15 minutes and at 3-5 hours post dose, were found in rats indicating that entacapone is subject to enterohepatic circulation and a single peak at 3 hours was found in dogs. A transformation of entacapone to its (Z)-isomer took place in both species studied, the transformation being minimal in rats but quite noticeable in dogs.|/MILK/ In animal studies, entacapone was excreted into maternal rat milk.|In rats and dogs, entacapone metabolites are predominantly excreted in the feces (two thirds as glucuronide or sulfate conjugates) and one third in the urine with less than 1.5% of the dose as unchanged entacapone. After the first hour 30-45% of the dose was recovered in the bile, with an enterohepatic circulation accounting for about 10% of the given radioactivity.|For more Absorption, Distribution and Excretion (Complete) data for ENTACAPONE (8 total), please visit the HSDB record page.

Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.|In rats and dogs, entacapone metabolites are predominantly excreted in the feces (two thirds as glucuronide or sulfate conjugates) and one third in the urine with less than 1.5% of the dose as unchanged entacapone. After the first hour 30-45% of the dose was recovered in the bile, with an enterohepatic circulation accounting for about 10% of the given radioactivity.|Entacapone is extensively metabolised in the liver in all species including humans, the main metabolic pathway being glucuronidation, sulfation and isomerisation from (E)- to (Z)-isomer (active metabolite). Similar pathways across species are the reduction of the C-C double bond of the side chain (less important in rat and in man) and the hydrolysis to 3,4-dihydroxy-5-nitrobenzaldehyde. The dissimilarities consists of amide N-dealkylation, nitro reduction and O-methylation (only in rats), amide hydrolysis and nitrile hydrolysis (only in dogs) and oxidative hydrolysis of one of the ethyl groups of the diethylamide group (only in man).|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.|Entacapone undergoes extensive metabolism, mainly in the liver. The main metabolic pathway of entacapone in humans is the isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive.|Entacapone has known human metabolites that include Entacapone 3-o-glucuronide.

0.4-0.7 hour|The elimination of entacapone is biphasic, with an elimination half-life of 0.4 hour to 0.7 hour based on the beta-phase and 2.4 hours based on the gamma-phase.|The overall elimination half-life of entacapone ranged from 30 minutes to 1 hour in dogs and from 1.5 to 3 hours in man.

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering 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. 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 a greater reduction in the manifestations of parkinsonian syndrome.|Comtan (entacapone) is a reversible, selective and mainly peripherally acting inhibitor of catechol-O-methyltransferase (COMT). Comtan has no antiparkinsonian effect of its own and is designed for concomitant administration with levodopa preparations. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a cathecol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. In the presence of a dopa decarboxylase (DDC) inhibitor, COMT becomes the major enzyme which is responsible for the metabolism of levodopa to 3-methoxy-4-hydroxy-l-phenylalanine (3-OMD). The mechanism of action of entacapone is believed to be related to its ability to inhibit COMT and thereby alter the plasma pharmacokinetics of levodopa. When administered with levodopa and a DDC inhibitor (carbidopa or benserazide), entacapone decreases the degradation of levodopa in the peripheral tissues further by inhibiting the metabolism of levodopa to 3-OMD through the COMT pathway. This leads to more sustained plasma concentrations of levodopa. 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 also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.

Management of Comtan overdose is symptomatic; there is no known antidote to Comtan. 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 Comtan is highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Comtan by decreasing its absorption and reabsorption from the gastrointestinal (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.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.|/HUMAN EXPOSURE STUDIES/ Catechol-O-methyltransferase (COMT) inhibition might be assumed to potentiate the effects of circulating catecholamines, particularly under conditions of enhanced catecholamine release. The purpose of the present study was to establish whether the novel COMT inhibitor, entacapone, changes hemodynamic responses and catecholamine metabolism during exercise. Entacapone was given orally to 12 healthy male subjects (age 23-30 years) in increasing single doses from 0 mg (control day) to 200 mg. A submaximal exercise test was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of noradrenaline, adrenaline, DHPG (3,4-dihydroxyphenylglycol), MHPG (3-methoxy-4-hydroxyphenyl-glycol) and, DOPAC (3,4-dihydroxyphenylacetic acid) in plasma were determined. Entacapone did not influence haemodynamics or ECG at rest or during exercise. Entacapone did not influence plasma catecholamine levels, either at rest or during exercise. However, it altered the metabolic profile of catecholamines, which was shown by increases in the plasma concentrations of the monoamine oxidase-dependent metabolites DHPG (by up to 100%) and DOPAC (by up to 53%), and by a decrease of the COMT-dependent metabolite MHPG (by up to 29%).|/SIGNS AND SYMPTOMS/ Catechol-O-methyltransferase (COMT) inhibition by entacapone treatment is dose-dependent. A massive overdose of Comtan (entacapone) may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols.|/SIGNS AND SYMPTOMS/ Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Comtan treatment or after starting or increasing the dose of Comtan. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of Comtan. Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Comtan|For more Human Toxicity Excerpts (Complete) data for ENTACAPONE (14 total), please visit the HSDB record page.

2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide

Oral: Tablets, film-coated, 200 mg, Comtan (Novartis).|Table: Entacapone Combination Preparations [Table#8243]

LC determination in plasma and urine.

Human drugs -> Comtan -> EMA Drug Category|Anti-Parkinson drugs -> Human pharmacotherapeutic group|Human drugs -> Comtess -> EMA Drug Category|Human drugs -> Entacapone Orion -> EMA Drug Category|Human drugs -> Levodopa/Carbidopa/Entacapone Orion -> EMA Drug Category|Nervous sytem -> Human pharmacotherapeutic group|Human drugs -> Stalevo -> EMA Drug Category|Human drugs -> Corbilta (previously Levodopa/Carbidopa/Entacapone Sandoz) -> EMA Drug Category|Human drugs -> Entacapone Teva -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients