Entacapone

When used with carbidopa and levodopa (Atamet, Parcopa, Sinemet), entacapone increases levels of levodopa in the body.

Entacapone is used together with carbidopa and levodopa to treat "wearing-off" symptoms of Parkinson's disease, such as stiffness, tremors, muscle spasms, and poor muscle control.

Entacapone may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use entacapone if you are allergic to it.

To make sure entacapone is safe for you, tell your doctor if you have:

• low blood pressure;
• liver disease; or
• a history of mental illness or psychosis.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medicine. Talk with your doctor if this occurs.

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for. You may need to have regular skin exams.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether entacapone passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Comtan® (entacapone) is available as tablets containing 200 mg entacapone.

Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson’s disease as an adjunct to levodopa and carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29. 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:

The inactive ingredients of the Comtan tablet are microcrystalline cellulose, mannitol, croscarmellose sodium, hydrogenated vegetable oil, hydroxypropyl methylcellulose, polysorbate 80, glycerol 85%, sucrose, magnesium stearate, yellow iron oxide, red iron oxide, and titanium dioxide.

Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of Comtan (entacapone) and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with Comtan and a non-selective MAO inhibitor.

Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline).

Drugs Metabolized By Catechol-O-Methyltransferase (COMT)

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

Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possible arrhythmias, and excessive changes in blood pressure.

Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty.

Falling Asleep During Activities Of Daily Living And Somnolence

Patients with Parkinson's disease treated with Comtan, which increases plasma levodopa levels, or with levodopa have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles). Some of these episodes resulted in accidents. Although many of these patients reported somnolence while on Comtan, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.

The risk of somnolence was increased (Comtan 2% and placebo 0%) in controlled studies. It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with Comtan. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with Comtan.

Before initiating treatment with Comtan, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as concomitant use of sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Comtan should ordinarily be discontinued (see DOSAGE AND ADMINISTRATION for guidance on discontinuing Comtan). If the decision is made to continue Comtan, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Serious side effects have been reported with entacapone. See the "Entacapone Precautions" section.

Common side effects of entacapone include the following:

• diarrhea
• nausea
• stomach pain
• dizziness
• drowsiness
• movements you cannot control
• change in the color of urine

This is not a complete list of entacapone side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Inhibits CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A only at very high concentrations.1 Inhibition of these isoenzymes not expected during clinical use.1

Drugs Metabolized by Catechol-O-methyltransferase

Possible increased heart rate, arrhythmias, and excessive changes in BP.1

Drugs Interfering with Biliary Excretion, Glucuronidation, and Intestinal β-Glucuronidase

Decreased entacapone excretion.1 7

Protein-bound Drugs

No binding displacement between entacapone and other highly protein bound drugs (e.g., warfarin, salicylic acid, phenylbutazone, diazepam).1

Specific Drugs

• Importance of taking entacapone as prescribed and not discontinuing abruptly.1

• Necessity of exercising caution when driving or operating machinery when entacapone is initiated.1 Caution when taking other CNS depressants.1

• Advise that entacapone may cause brownish orange discoloration of urine; not clinically important.1

• Advise that hallucinations, nausea, and increased dyskinesia can occur.1

• Advise patients not to rise rapidly after prolonged sitting or lying down, especially during first few weeks of therapy.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving entacapone and of advising them of the importance of reporting such urges.1 8

• Importance of frequent monitoring for melanoma and periodic dermatologic examinations by a dermatologist.1 8

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Take entacapone only as directed by your doctor, to help your condition as much as possible. Do not take more or less of it, and do not take it more or less often than your doctor ordered.

Take entacapone with or without food.

Dosing

The dose of entacapone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of entacapone. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For Parkinson's disease:
    • Adults—200 milligrams (mg) with each levodopa/carbidopa dose. Your doctor may increase your dose up to 8 times per day for a total dose of 1600 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of entacapone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Tell all of your health care providers that you take entacapone. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• The chance of a type of skin cancer called melanoma may be raised in people with Parkinson's disease. It is not known if entacapone may also raise the chance. Have skin exams while you take this medicine. Talk with your doctor.
• Do not stop taking entacapone all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop this medicine, you will want to slowly stop it as ordered by your doctor.
• It is common to have diarrhea with entacapone. Sometimes, diarrhea has been very bad and rarely has led to needing to go to the hospital. Very bad diarrhea may lead to weight loss, dehydration, or low potassium levels. Talk with your doctor.
• If you get diarrhea, you will need to make sure to avoid getting dehydrated. Drink plenty of fluids and watch for weight loss. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Entacapone is a reversible and selective inhibitor of catechol-O-methyltransferase (COMT). When entacapone is taken with levodopa, the pharmacokinetics are altered, resulting in more sustained levodopa serum levels compared to levodopa taken alone. The resulting levels of levodopa provide for increased concentrations available for absorption across the blood-brain barrier, thereby providing for increased CNS levels of dopamine, the active metabolite of levodopa.

Absorption

Rapid

Distribution

IV: Vdss: 20 L

Metabolism

Isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer

Excretion

Feces (90%); urine (10%)

U.S. labeling: There are no dosage adjustments provided in the manufacturer's labeling. Treat with caution and monitor carefully; AUC and Cmax may possibly be doubled.

Canadian labeling: Use is contraindicated.

Concerns related to adverse effects:

• Abnormal thinking/behavioral changes: Abnormal thinking and behavior changes have been reported and may include aggressive behavior, agitation, confusion, delirium, delusions, disorientation, paranoid ideation, and psychotic-like behavior.

• Diarrhea: Has been associated with delayed development of diarrhea (usual onset after 4 to 12 weeks); use with caution in patients with lower gastrointestinal disease or an increased risk of dehydration. Diarrhea may be a sign of drug-induced colitis (primarily lymphocytic). Monitor for weight loss. Discontinue use with prolonged diarrhea.

• Dyskinesia: New-onset or exacerbation of preexisting dyskinesia may occur when used as an adjunct to levodopa. Decreasing the dose of levodopa may ameliorate these side effects in some cases.

• Hallucinations: May cause hallucinations.

• Impulse control disorders: Compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), intense urges to spend money uncontrollably, and other intense urges have been reported. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed. The Canadian labeling contraindicates use in patients with suspicious, undiagnosed skin lesions or history of melanoma.

• Neuroleptic malignant syndrome: Entacapone, in conjunction with other drug therapy that alters brain biogenic amine concentrations (eg, MAO inhibitors, SSRIs), has been associated with a syndrome resembling neuroleptic malignant syndrome (hyperpyrexia and confusion - some fatal) on abrupt withdrawal or dosage reduction. Concomitant use of entacapone and nonselective MAO inhibitors should be avoided.

• Orthostatic hypotension: May cause orthostatic hypotension and syncope.

• Pleural/retroperitoneal fibrosis: Dopaminergic agents from the ergot class have been associated with fibrotic complications, such as retroperitoneal fibrosis, pulmonary infiltrates or pleural effusion and thickening. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. It is unknown whether nonergot, pro-dopaminergic agents like entacapone confer this risk.

• Rhabdomyolysis: Severe rhabdomyolysis has been reported with use.

• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs and may occur as late as up to 1 year after initiation of treatment. Monitor for daytime somnolence or preexisting sleep disorder. Use caution in the presence of sleep disorders, with other CNS depressants, sedating agents, psychoactive drugs or ethanol. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Cardiovascular disease: The Canadian product labeling notes to use with caution in patients with cardiovascular disease, including a history of myocardial infarction (MI) and arrhythmias; MI and other ischemic adverse events have been observed in clinical trials.

• Hepatic impairment: Use with caution in patients with hepatic impairment or biliary obstruction. The Canadian labeling contraindicates use in hepatic impairment.

• Psychotic disorders: Avoid use in patients with major psychotic disorder due to the risk of exacerbating psychosis. Many treatments for psychosis may exacerbate the symptoms of Parkinson disease and may also decrease the effectiveness of entacapone.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Other warnings/precautions:

• Discontinuation of therapy: Do not withdraw therapy abruptly.

• Urine discoloration: Urine may appear dark in color (brownish orange) during therapy.

Signs and symptoms of Parkinson's disease; liver function tests, blood pressure, patient's mental status and impulse control disorders; daytime sleepiness; serum iron (if signs of anemia); weight loss (patients experiencing diarrhea); signs and symptoms of neuroleptic malignant syndrome if abrupt discontinuation required; dermatologic examination (regularly while on therapy).

Canadian labeling (additional monitoring recommendations): Cardiac function with initial dosage adjustments and periodically during prolonged therapy (patients with history of MI or arrhythmia)

Commonly reported side effects of entacapone include: urine discoloration. See below for a comprehensive list of adverse effects.