Entacapone
   HOME

TheInfoList



OR:

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
. Entacapone together with
levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...
and
carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...
allows levodopa to have a longer effect in the brain and reduces Parkinson's disease
signs and symptoms Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...
for a greater length of time than levodopa and carbidopa therapy alone. Entacapone is a selective and reversible inhibitor of the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
catechol-''O''-methyltransferase (COMT). When taken together with levodopa (L-DOPA) and carbidopa, entacapone stops COMT from breaking down levodopa, resulting in an overall increase of levodopa remaining in the brain and body. Entacapone does not cross into the brain and hence does not inhibit COMT there. Carbidopa/levodopa/entacapone (Stalevo), a medication developed by Orion Pharma and marketed by
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
, is a single tablet
formulation Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula ...
that contains levodopa, carbidopa, and entacapone.


Medical uses

Entacapone is used in addition to levodopa and carbidopa for people with Parkinson's disease to treat the signs and symptoms of end-of-dose "wearing-off." "Wearing-off" is characterized by the re-appearance of both
motor An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy. Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power gene ...
and non-motor symptoms of Parkinson's disease occurring towards the end of a previous levodopa and carbidopa dose. In clinical trials, entacapone has not been shown to slow progression or reverse Parkinson's disease. Entacapone is an orally active drug that can be taken with or without food.


Pregnancy and breastfeeding

Pregnancy category C: risk is not ruled out. Although there have been animal studies that showed that entacapone was excreted into maternal rat milk, there have been no studies with
human breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a va ...
. Caution is advised for mothers taking entacapone while breastfeeding or during pregnancy.


Children

Entacapone safety and efficacy have not been assessed in
infant In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...
s or children.


Liver problems

Biliary A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. The bile duct is separated into three main parts: the fundus (superior), the body (middle), and the neck (inferior). Bile is requ ...
excretion is the major route of
excretion Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...
for entacapone. People with liver dysfunction may require additional caution and more frequent liver function monitoring while taking entacapone.


Kidney problems

There are no significant considerations for people with poor kidney function taking entacapone.


Contraindications

There is a high risk for allergic reactions for people who are hypersensitive to entacapone. Potential limiting conditions to consider before starting entacapone include: * History of
allergic reaction Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
to entacapone * History of
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
, liver dysfunction, or
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
* Current or planned
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
* Current or planned
surgeries Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery ...


Side effects

The following
side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...
have been reported by people with Parkinson's disease treated with entacapone: * Abdominal pain * Nausea * Vomiting * Fatigue * Dry mouth * Back ache


Movement problems

The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone. This drug may cause or worsen
dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
for people with Parkinson's disease treated together with levodopa and carbidopa. In particular, " peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.


Diarrhea

10% of patients taking entacapone have been shown to experience
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
. Diarrhea may occur within 4–12 weeks of initial entacapone use but resolves after discontinuation of the drug. Use of entacapone in the presence of diarrhea can also be associated with
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
, low
potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
levels, and
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
. In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.


Urine color

10% of people taking entacapone experience a change in urine color to orange, red, brown, or black. This side effect is due to entacapone metabolism and excretion in the urine and shown to not be harmful.


Sudden sleep onset

People have reported sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2% increased risk of
somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...
compared to
placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...
.


Low blood pressure

Episodes of
orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
have been shown to be more common at the start of entacapone use due to increased levels of levodopa.


Behavior problems

Post-marketing data shows that entacapone may change or worsen
mental status The mental status examination (MSE) is an important part of the clinical assessment process in neurological and psychiatric practice. It is a structured way of observing and describing a patient's psychological functioning at a given point in ...
, leading to behaviors such as
delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
s, agitation, confusion, and
delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
. People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.


Interactions

In studies, entacapone has shown a low potential for interaction with other drugs. In theory, it could interact with
MAO inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...
s,
tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
s and noradrenaline reuptake inhibitors because they also increase
catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...
levels in the body, with drugs being metabolized by COMT (for example
methyldopa Methyldopa, also known as α-methyl-L-DOPA and sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blo ...
,
dobutamine Dobutamine is a medication used in the treatment of cardiogenic shock (as a result of inadequate tissue perfusion) and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection ...
, apomorphine,
adrenaline Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
, and
isoprenaline Isoprenaline, also known as isoproterenol and sold under the brand name Isuprel among others, is a sympathomimetic medication which is used in the treatment of acute bradycardia (slow heart rate), heart block, and rarely for asthma, among other ...
), with iron because it could form
chelate Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...
s, with substances binding to the same
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
site in the blood plasma (for example
diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
and
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It can be taken oral administration, ...
), and with drugs being metabolized by the liver enzyme
CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...
(for example
warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
). None of the medications tested in studies have shown clinically relevant interactions, except perhaps warfarin for which a 13% ( CI90: 6–19%) increase in INR was seen when combined with entacapone.


Pharmacology


Mechanism of action

Entacapone is a selective and reversible inhibitor of catechol-''O''-methyltransferase (COMT). COMT eliminates biologically active
catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...
s present in
catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...
s (
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
,
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
) and their
hydroxylated In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s. When administered with a decarboxylase inhibitor, COMT acts as the major metabolizing enzyme for levodopa and metabolizes it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and in the
periphery Periphery or peripheral may refer to: Music *Periphery (band), American progressive metal band * ''Periphery'' (album), released in 2010 by Periphery *"Periphery", a song from Fiona Apple's album '' The Idler Wheel...'' Gaming and entertainme ...
. For the treatment of Parkinson's disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor,
carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...
. Entacapone is peripherally selective and inhibits COMT in the body but not in the brain. As a result, entacapone inhibits the peripheral metabolism of levodopa, thus increasing plasma levels of levodopa. This causes more constant dopaminergic stimulation in order to reduce the
signs and symptoms Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...
presented in the disease.


Pharmacokinetics


Absorption

The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive
first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...
. Absolute oral
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
(''F'') is 35%.


Distribution

The
volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
(Vd) after
intravenous injection Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
is approximately 20 liters. 98% of the circulating entacapone is bound to serum
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
, which limits its
distribution Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...
into tissues. Entacapone has low
lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are called lipophilic (translated ...
and does not significantly cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
. As a result, it is a
peripherally selective drug Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest o ...
and does not act in the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
.


Metabolism and elimination

Entacapone is primarily metabolized to its
glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...
in the liver, and 5% are converted into the ''Z''-isomer. It has a
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine.


Research


Restless legs syndrome

Entacapone, in conjunction with levodopa and carbidopa, was under development for use in the treatment of
restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...
(RLS), but development was discontinued.


References

{{Portal bar , Medicine Antiparkinsonian agents Carboxamides Catechols Catechol-O-methyltransferase inhibitors Drugs developed by Novartis Nitriles Nitrophenol derivatives Peripherally selective drugs