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  • CLASSES

    Anti-Parkinson drugs, COMT Inhibitors

    BOXED WARNING

    Abrupt discontinuation, dyskinesia, rhabdomyolysis

    Tolcapone is contraindicated in patients with a history of non-traumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to the drug. Cases of severe rhabdomyolysis have occurred, including one case of multiorgan system failure and eventual death. Tolcapone may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinetic movements and is one of the most common side effects of the drug. The boxed warning for tolcapone recommends that the drug be used with caution in patients with severe dyskinesia or dystonia, as severe prolonged motor activity including dyskinesia may account for some cases of rhabdomyolysis. Abrupt discontinuation or dose reduction of tolcapone should also be avoided if possible; closely monitor patients and adjust other dopaminergic treatments as necessary during tolcapone discontinuation. In clinical trials of tolcapone, 4 cases of a symptom complex resembling the neuroleptic malignant syndrome (e.g., elevated temperature, muscular rigidity, and altered consciousness, confusion), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported postmarketing. It is difficult to determine if tolcapone played a role in the pathogenesis of these events because these patients also received several concomitant medications affecting the central nervous system.

    Hepatic disease, hepatotoxicity

    Tolcapone is contraindicated in patients with hepatic disease or in patients previously withdrawn from tolcapone due to evidence of tolcapone-induced hepatotoxicity (hepatocellular injury). Tolcapone should not be initiated in patients with two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (ULN). Due to the risk of hepatotoxicity and potentially fatal, acute fulminant hepatic failure, tolcapone should ordinarily only be used in patients with Parkinson's disease on L-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Patients who fail to show substantial clinical benefit within the first 3 weeks of tolcapone therapy should be withdrawn from the medication due to the risk of severe hepatic toxicity with continued treatment. Cases of severe hepatocellular injury, including cases of fatal hepatic failure resulting in death, have been reported in postmarketing use of tolcapone. Three cases of fatal hepatic injury have been reported in approximately 40,000 patients treated with tolcapone. The incidence is 10- to 100-fold higher than the normal incidence of hepatic failure in the general population. Liver function tests (LFTs) should be determined at baseline and monitored periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy, and thereafter as is clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgment. If the dose is increased to 200 mg three times per day, LFT monitoring should take place before increasing the dose and every 2 to 4 weeks for the following 6 months. After 6 months, periodic monitoring is recommended at intervals deemed clinically relevant. It is recommended that tolcapone should be discontinued if hepatic enzymes exceed 2 times the ULN or if any clinical signs or symptoms suggestive of hepatic injury such as jaundice or cholestasis are present. Other symptoms that may be suggestive of hepatic impairment include right upper quadrant pain, pruritus, clay-colored stools, tiredness, persistent nausea, loss of appetite, or dark urine. Do not re-introduce tolcapone following recovery.

    DEA CLASS

    Rx

    DESCRIPTION

    Peripheral and centrally acting oral COMT inhibitor; improves levodopa availability in the CNS; more potent than entacapone
    Used for adults with Parkinson's disease as an adjunct to levodopa/carbidopa
    Less favorable side effect profile vs. entacapone; boxed warning exists in labeling for hepatotoxicity and risk for hepatocellular injury and liver failure

    COMMON BRAND NAMES

    Tasmar

    HOW SUPPLIED

    Tasmar/Tolcapone Oral Tab: 100mg, 200mg

    DOSAGE & INDICATIONS

    For use as adjunctive treatment to levodopa and carbidopa for the treatment of signs and symptoms of idiopathic Parkinson's disease.
    Oral dosage
    Adults

    100 mg PO 3 times per day, initially. In clinical trials, the first dose of the day of tolcapone was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of tolcapone were given approximately 6 and 12 hours later. Do not increase to 200 mg PO 3 times per day unless the incremental clinical benefit is likely to exceed the potential increased risk of hepatotoxicity. Max: 600 mg/day PO. If there is no clinical benefit at any dose after a total of 3 weeks of treatment, tolcapone should be discontinued.

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Geriatric

    600 mg/day PO.

    Adolescents

    Safety and efficacy have not been established. 

    Children

    Safety and efficacy have not been established. 

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Tolcapone is contraindicated in patients with liver disease. Do not initiate tolcapone in a patient who exhibits clinical evidence of liver disease or 2 SGPT/ALT or SGOT/AST values greater than the upper limit of normal (ULN).
    During treatment: Discontinue tolcapone if liver enzymes exceed 2 times the ULN or if clinical signs and symptoms suggest the onset of hepatic dysfunction.

    Renal Impairment

    CrCl 25 mL/minute or greater: No dose adjustment is necessary.
    CrCl less than 25 mL/minute: Use with caution. the safety of tolcapone has not been studied. Tolcapone is not expected to be removed by hemodialysis.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Tolcapone may be administered with or without food.
    During clinical trials, the first dose of the day of tolcapone was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of tolcapone were given approximately 6 and 12 hours later.

    STORAGE

    Tasmar:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tolcapone is contraindicated in patients with a known hypersensitivity to tolcapone or its ingredients.

    Abrupt discontinuation, dyskinesia, rhabdomyolysis

    Tolcapone is contraindicated in patients with a history of non-traumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to the drug. Cases of severe rhabdomyolysis have occurred, including one case of multiorgan system failure and eventual death. Tolcapone may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinetic movements and is one of the most common side effects of the drug. The boxed warning for tolcapone recommends that the drug be used with caution in patients with severe dyskinesia or dystonia, as severe prolonged motor activity including dyskinesia may account for some cases of rhabdomyolysis. Abrupt discontinuation or dose reduction of tolcapone should also be avoided if possible; closely monitor patients and adjust other dopaminergic treatments as necessary during tolcapone discontinuation. In clinical trials of tolcapone, 4 cases of a symptom complex resembling the neuroleptic malignant syndrome (e.g., elevated temperature, muscular rigidity, and altered consciousness, confusion), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported postmarketing. It is difficult to determine if tolcapone played a role in the pathogenesis of these events because these patients also received several concomitant medications affecting the central nervous system.

    Hepatic disease, hepatotoxicity

    Tolcapone is contraindicated in patients with hepatic disease or in patients previously withdrawn from tolcapone due to evidence of tolcapone-induced hepatotoxicity (hepatocellular injury). Tolcapone should not be initiated in patients with two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (ULN). Due to the risk of hepatotoxicity and potentially fatal, acute fulminant hepatic failure, tolcapone should ordinarily only be used in patients with Parkinson's disease on L-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Patients who fail to show substantial clinical benefit within the first 3 weeks of tolcapone therapy should be withdrawn from the medication due to the risk of severe hepatic toxicity with continued treatment. Cases of severe hepatocellular injury, including cases of fatal hepatic failure resulting in death, have been reported in postmarketing use of tolcapone. Three cases of fatal hepatic injury have been reported in approximately 40,000 patients treated with tolcapone. The incidence is 10- to 100-fold higher than the normal incidence of hepatic failure in the general population. Liver function tests (LFTs) should be determined at baseline and monitored periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy, and thereafter as is clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgment. If the dose is increased to 200 mg three times per day, LFT monitoring should take place before increasing the dose and every 2 to 4 weeks for the following 6 months. After 6 months, periodic monitoring is recommended at intervals deemed clinically relevant. It is recommended that tolcapone should be discontinued if hepatic enzymes exceed 2 times the ULN or if any clinical signs or symptoms suggestive of hepatic injury such as jaundice or cholestasis are present. Other symptoms that may be suggestive of hepatic impairment include right upper quadrant pain, pruritus, clay-colored stools, tiredness, persistent nausea, loss of appetite, or dark urine. Do not re-introduce tolcapone following recovery.

    Orthostatic hypotension, syncope

    Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the occurrence of orthostatic hypotension or syncope. Patients with orthostasis at baseline were more likely than patients without symptoms to have orthostatic hypotension during clinical trials. Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Advise patients to rise slowly, especially after long periods of sitting or lying down. Hypotension may be more likely when patients first start treatment.

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Tolcapone has the potential to cause drowsiness or somnolence. Tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa; levodopa products. Patients taking carbidopa; levodopa products alone or with other dopaminergic medications have reported sudden episodes of falling asleep without prior warning of sleepiness while engaged in activities of daily living. In some cases, excessive drowsiness has resulted in auto accidents or other harmful events. Although many of these patients reported somnolence while on tolcapone, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events 1 year after the initiation of treatment. Patients should be advised of this effect and be instructed to use extreme caution when driving or operating machinery or performing other tasks that require alertness while receiving tolcapone. Reassessment for drowsiness or oversedation is necessary throughout tolcapone therapy. Sleep disorders, coadministration with other CNS depressants including ethanol ingestion, or other interacting medications may increase the risk of falling asleep while on this medication. Patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Consider discontinuing tolcapone in patients that develop significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If a decision is made to continue the drug, patients should be advised to avoid driving or other potentially dangerous activities. There is insufficient information to establish if dose reduction will eliminate sudden episodes of falling asleep.

    Impulse control symptoms

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable impulse control symptoms, such as urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. Causality due to dopaminergic agents has not been established; however, in some cases, the urges stopped after the dose was reduced or the drug was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with tolcapone. Dose reduction or discontinuation should be considered in those who experience these effects.

    Hematuria

    Tolcapone should be used with caution in patients with preexisting hematuria. Hematuria has been associated with tolcapone therapy in placebo-controlled clinical trials.

    Behavioral changes, psychosis

    Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during tolcapone treatment or after starting or increasing the dose of tolcapone. Hallucinations have also been reported in patients receiving tolcapone. In general, patients with a major psychotic disorder should not be treated with tolcapone 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 tolcapone.

    Diarrhea

    Tolcapone should be used cautiously in patients with preexisting diarrhea. Diarrhea was the most common adverse reaction leading to discontinuation of tolcapone therapy, and in rare cases, hospitalization. Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite). No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown. It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).

    Renal impairment

    No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution. While renal tubular damage has been reported in some animal studies with tolcapone, the relevance of these findings to humans is not known.

    Melanoma

    Epidemiological studies have shown that patients with Parkinson's disease have a 2- to 6-fold higher risk of developing melanoma than the general population. It is unclear if this increased risk is disease-related or associated with other factors such as the medications (e.g. tolcapone) used to treat Parkinson's disease. Therefore, it is recommended that a qualified practitioner (e.g., dermatologist) monitor for melanomas on a regular basis during tolcapone use for any indication. In addition, patients should be instructed to regularly monitor for skin changes that may indicate the presence of melanoma and to promptly report these changes to their provider.

    Pregnancy

    There is no experience from clinical studies regarding the use of tolcapone during human pregnancy. The low molecular weight of the drug suggests that placental transfer is likely. There have been postmarketing cases of severe hepatocellular injury with use of tolcapone, including fulminant liver failure resulting in death, and the potential risk to the developing fetus is unknown. Tolcapone is always given with levodopa/carbidopa, which has been known to cause visceral and skeletal malformations in animals. There was no evidence of teratogenicity or impaired fertility in animals during use of tolcapone alone; however, the highest dose was associated with maternal toxicity, including decreased weight gain and death. During use in rats during late gestation and throughout lactation, decreased litter size and impaired growth and learning were observed in the female offspring. Treatment in rabbits during organogenesis resulted in an increased rate of abortion and maternal toxicity. During animal studies evaluating a combination of tolcapone, levodopa, and carbidopa during organogenesis at half the expected human exposure of tolcapone and 6 times the expected levodopa human exposure, there was an increased incidence of fetal anomalies (primarily external and skeletal digit defects) compared to levodopa/carbidopa treatment without tolcapone. In rats, the three-drug combination at half the expected tolcapone human exposure or higher and 21 times the expected levodopa human exposure or greater was associated with decreased fetal body weights; however, no effect on weight was observed during use of tolcapone alone. Because human data are unavailable and animal reproduction studies are not always predictive of human response, tolcapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effects of tolcapone in labor and delivery are unknown.

    Abrupt discontinuation

    During tolcapone clinical trials, 3 cases of pleural effusion, 1 with pulmonary fibrosis, occurred. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion). Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., tolcapone) that increase dopaminergic activity can cause them is unknown.

    Breast-feeding

    According to the manufacturer, it is unknown if tolcapone is excreted in human milk; however it is excreted into maternal milk in rats. The molecular weight of the drug suggests that excretion into human breast milk is likely. Due to the possibility that tolcapone may be excreted into human milk and the risk for serious side effects such as liver injury, the manufacturer recommends caution when tolcapone is administered to breast-feeding women. Because tolcapone is always administered with carbidopa/levodopa, breast-feeding precautions for these agents should also be followed. In addition, tolcapone enhances levodopa bioavailability, potentially exposing the nursing infant to increased levels of levodopa. If possible, tolcapone should be avoided during breast-feeding. Until more data become available, entacapone may be the preferred COMT inhibitor during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    In clinical trials of tolcapone, there were generally no consistent age-related trends in safety parameters. However, geriatric patients older than 75 years may be more likely to develop hallucinations and less likely to develop dystonia than patients less than 75 years. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications.

    Children, infants

    There is no identified potential use of tolcapone in pediatric patients less than 18 years of age. Safe and effective use is not established in adolescents, children or infants.

    MAOI therapy, surgery

    The administration of non-selective monoamine oxidase inhibitor therapy (MAOI therapy) is generally contraindicated with tolcapone. Monoamine oxidase (MAO) and Catechol-O-Methyltransferase (COMT) are the 2 major enzyme systems involved in the metabolism of catecholamines. Concomitant use of non-selective MAOIs with tolcapone may result in hypertensive crisis. Nonselective MAOIs are recommended to be discontinued at least 2 weeks prior to initiating therapy with tolcapone. Selective MAO-B inhibitors and other standard drugs for Parkinson's disease may be used concomitantly with tolcapone; however, dosage adjustments of therapies may be required. Drugs known to be metabolized by COMT should be administered with caution in patients receiving tolcapone regardless of the route of administration (including inhalation), as interactions may result in increased heart rate, arrhythmia, and/or increased blood pressure. Patients should inform their surgeon and anesthesiologist of the use of tolcapone prior to surgery, as COMT inhibitors may interact with some medications used in surgical procedures. If a patient requires general anesthesia for surgery, tolcapone may be continued as long as the patient is permitted to take fluids and medication by mouth. Cases of neuroleptic malignant syndrome have been reported post-surgery so close monitoring is warranted; reinstitute tolcapone therapy as soon as possible after the procedure.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0.1-1.0
    stroke / Early / 0.1-1.0
    oliguria / Early / 0.1-1.0
    cardiac arrest / Early / 0.1-1.0
    heart failure / Delayed / 0.1-1.0
    pulmonary embolism / Delayed / 0.1-1.0
    atrial fibrillation / Early / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    erythema multiforme / Delayed / 0.1-1.0
    ocular hemorrhage / Delayed / 0.1-1.0
    cholecystitis / Delayed / 0-0.1
    peptic ulcer / Delayed / 0-0.1
    pericardial effusion / Delayed / 0-0.1
    thrombosis / Delayed / 0-0.1
    apnea / Delayed / 0-0.1
    rhabdomyolysis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known

    Moderate

    dyskinesia / Delayed / 42.0-51.0
    dystonic reaction / Delayed / 19.0-22.0
    orthostatic hypotension / Delayed / 13.0-14.0
    confusion / Early / 10.0-11.0
    hallucinations / Early / 8.0-10.0
    constipation / Delayed / 6.0-8.0
    hematuria / Delayed / 2.0-5.0
    elevated hepatic enzymes / Delayed / 1.0-3.0
    chest pain (unspecified) / Early / 1.0-3.0
    dyspnea / Early / 3.0-3.0
    hypotension / Rapid / 2.0-2.0
    oral ulceration / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    amnesia / Delayed / 0.1-1.0
    hostility / Early / 0.1-1.0
    myoclonia / Delayed / 0.1-1.0
    euphoria / Early / 0-1.0
    choreoathetosis / Delayed / 0.1-1.0
    mania / Early / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    hypertension / Early / 0.1-1.0
    angina / Early / 0.1-1.0
    hypertonia / Delayed / 0-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    furunculosis / Delayed / 0.1-1.0
    bleeding / Early / 1.0-1.0
    cataracts / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    dehydration / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    edema / Delayed / 1.0-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    psychosis / Early / 0.1-1.0
    delirium / Early / 0-1.0
    meningitis / Delayed / 0-0.1
    encephalopathy / Delayed / 0-0.1
    hypoxia / Early / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    hyperesthesia / Delayed / 1.0
    depression / Delayed / 1.0
    dysarthria / Delayed / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    urinary incontinence / Early / 1.0
    palpitations / Early / 1.0
    flank pain / Delayed / 1.0
    withdrawal / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    sudden sleep onset / Delayed / Incidence not known

    Mild

    nausea / Early / 30.0-35.0
    insomnia / Early / 24.0-25.0
    anorexia / Delayed / 19.0-23.0
    diarrhea / Early / 16.0-18.0
    muscle cramps / Delayed / 17.0-18.0
    drowsiness / Early / 14.0-18.0
    dizziness / Early / 6.0-13.0
    headache / Early / 10.0-11.0
    vomiting / Early / 8.0-10.0
    urine discoloration / Early / 2.0-7.0
    hyperhidrosis / Delayed / 4.0-7.0
    fatigue / Early / 3.0-7.0
    abdominal pain / Early / 5.0-6.0
    xerostomia / Early / 5.0-6.0
    syncope / Early / 4.0-5.0
    dyspepsia / Early / 3.0-4.0
    flatulence / Early / 2.0-4.0
    influenza / Delayed / 3.0-4.0
    paresthesias / Delayed / 1.0-3.0
    hyperkinesis / Delayed / 2.0-3.0
    arthropathy / Delayed / 1.0-2.0
    nasal congestion / Early / 1.0-2.0
    hypersalivation / Early / 0.1-1.0
    irritability / Delayed / 1.0-1.0
    libido increase / Delayed / 0.1-1.0
    libido decrease / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    hiccups / Early / 0.1-1.0
    cough / Delayed / 0.1-1.0
    fever / Early / 0-1.0
    rhinitis / Early / 0.1-1.0
    laryngitis / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    alopecia / Delayed / 0-1.0
    seborrhea / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    otalgia / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    malaise / Early / 0-1.0
    chills / Rapid / 0.1-1.0
    agitation / Early / 1.0-1.0
    paranoia / Early / 0.1-1.0
    vertigo / Early / 1.0
    tremor / Early / 1.0
    emotional lability / Early / 1.0
    myalgia / Early / 1.0
    pharyngitis / Delayed / 1.0
    rash / Early / 1.0
    tinnitus / Delayed / 1.0

    DRUG INTERACTIONS

    Acetaminophen; Tramadol: (Moderate) COMT inhibitors can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Alprazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Amoxapine: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Articaine; Epinephrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as epinephrine, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with COMT inhibitors can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with COMT inhibitors can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    atypical antipsychotic: (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors.
    Barbiturates: (Moderate) COMT inhibitors, like entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation. Agents that may cause additive sedation when given concurrently with tolcapone include the barbiturates. The risk for adverse effects may increase, and patients should use caution in driving or other hazardous tasks until the effects of the drugs are known.
    Benzodiazepines: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Buspirone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including buspirone, due to the possibility of additive sedation.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, such as the COMT inhibitors.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, such as the COMT inhibitors.
    Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Chlordiazepoxide; Clidinium: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Chlorpromazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (e.g., increased sedation) may occur when clobazam is combined with other CNS depressants such as tolcapone.
    Clonazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Clorazepate: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Codeine; Phenylephrine; Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Codeine; Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as tolcapone, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexmethylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of dexmethylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme decreases the metabolism of levodopa to metabolites, thereby increasing the dopaminergic effects of the drug. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of dexmethylphenidate and a COMT inhibitor.
    Dextromethorphan; Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Diazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Dobutamine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as dobutamine, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Dopamine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as dopamine, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Dronabinol, THC: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including dronabinol, due to the possibility of additive sedation.
    Droperidol: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including droperidol, due to the possibility of additive sedation.
    Epinephrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as epinephrine, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Estazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone or concomitantly administered drugs with sedative properties (e.g., COMT inhibitors) should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Moderate) Tolcapone should be given cautiously with other agents that cause CNS depression, such as alcohol, due to the possibility of additive sedation.
    Fluphenazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Flurazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Gabapentin: (Moderate) CNS depressive effects, such as drowsiness or dizziness, may increase when antiparkinsonian agents, such as tolcapone, are given concomitantly with gabapentin. Counsel patients to limit activity until they are aware of how coadministration affects them.
    Haloperidol: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including haloperidol, due to the possibility of additive sedation.
    Heterocyclic antidepressants: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as methyldopa, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Isocarboxazid: (Severe) At least 14 days should elapse between the discontinuation of isocarboxazid, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and isocarboxazid may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects.
    Isoniazid, INH: (Major) Patients should generally not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Patients should generally not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism.
    Isoniazid, INH; Rifampin: (Major) Patients should generally not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions. Monoamine oxidase and catechol-O-methyltransferase are the 2 major enzymes involved in the metabolism of catecholamines. It is possible that the combination of a COMT inhibitor and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism.
    Isoproterenol: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as isoproterenol, should be administered cautiously in patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, such as the COMT inhibitors.
    Linezolid: (Major) Avoid the concomitant use of entacapone or tolcapone in combination with a non-selective monoamine oxidase inhibitor such as linezolid. Monoamine oxidase and catechol-O-methyltransferase are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the co-administration of entacapone or tolcapone with linezolid would result in inhibition of normal catecholamine metabolism and possible toxicity. Typically, at least 14-days should elapse between the discontinuation of the non-selective MAOI and the use of entacapone or tolcapone to avoid potential interactions.
    Lorazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Loxapine: (Major) Entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, such as loxapine, due to the possibility of additive sedation.
    Maprotiline: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Meperidine; Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including COMT inhibitors. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed.
    Mesoridazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Methyldopa: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as methyldopa, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Methylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme reduces the metabolism of levodopa to metabolites, thereby prolonging the dopaminergic effects of levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of methylphenidate and a COMT inhibitor.
    Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist. It should be noted that the therapeutic response to COMT inhibitors (entacapone and tolcapone) may be diminished during use of a centrally acting dopamine antagonist. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Metoclopramide is contraindicated with other drugs that are likely to cause extrapyramidal effects since the risk of these effects may be increased. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as COMT inhibiotrs, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Midazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Mirtazapine: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Molindone: (Major) In general, antipsychotics can worsen the motor symptoms of Parkinson's disease thereby decreasing the overall effectiveness of antiparkinsonian agents. In addition, Parkinson's treatments like tolcapone may cause drowsiness which can result in additive CNS effects with molindone. Therefore, molindone should be avoided in patients receiving medications for Parkinson's disease unless the benefit of molindone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Nefazodone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation.
    Norepinephrine: (Moderate) Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. Norepinephrine is metabolized by catechol-O-methyltransferase (COMT) and should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone.
    Opiate Agonists: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Opiate Agonists-Antagonists: (Moderate) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Oxazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as tolcapone.
    Perphenazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Perphenazine; Amitriptyline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Phenelzine: (Severe) At least 14 days should elapse between the discontinuation of phenelzine, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and phenelzine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects.
    Phenothiazines: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Phenylephrine; Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Pimozide: (Major) Entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, such as pimozide, due to the possibility of additive sedation.
    Pramipexole: (Moderate) The use of other parkinson's medications such as entacapone in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
    Pregabalin: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Prilocaine; Epinephrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as epinephrine, should be administered cautiously in patients receiving COMT-inhibitors like entacapone or tolcapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
    Procarbazine: (Major) Procarbazine has some non-selective MAO inhibiting activity. Typically, at least 14 days should elapse between the discontinuation of the non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Patients should ordinarily not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity. MAO and COMT are the 2 major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the combination of COMT-inhibitors and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism.
    Prochlorperazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Promethazine: (Major) Phenothiazines like promethazine may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Medications like entacapone, tolcapone, pramipexole or ropinirole may also cause additive drowsiness when combined with promethazine. In general, the use of a phenothiazine-type drug should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. Patients taking these drugs should be carefully observed for loss of therapeutic response.
    Quazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Racepinephrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as racepinephrine inhalations , should be administered cautiously in patients receiving COMT inhibitors like entacapone, tolcapone, or combinations containing these drugs such as carbidopa; levodopa; entacapone. If a patient is taking a COMT-inhibitor, then they should seek health care professional advice prior to the use of racepinephrine. Concomitant use may result in increased heart rate, possibly arrhythmias, and excessive changes in blood pressure. A single 400 mg dose of entacapone given with intravenous epinephrine has produced changes in heart rate and blood pressure. Ventricular tachycardia was noted in one healthy volunteer during an interaction study with epinephrine infusion and oral entacapone administration.
    Rasagiline: (Moderate) Typically, COMT inhibitors should not be used with non-selective MAOIs. However, rasagiline appears to have selective properties for MAO-B, and stable doses of entacapone were used together with rasagiline in clinical trials.
    Ropinirole: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression due to the possibility of additive sedation.
    Sedating H1-blockers: (Moderate) COMT inhibitors, such as entacapone or tolcapone, should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation.
    Selegiline: (Moderate) These drugs may be taken together in the treatment of Parkinson's disease. No specific drug-drug pharmacokinetic interactions have been noted. However, when adding additional therapies for this disease, the practitioner should be alert to adverse effects related to dopaminergic and serotonergic activities, and the potential need for dosage titrations based on drug tolerance and effectiveness.
    Skeletal Muscle Relaxants: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tapentadol: (Moderate) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the CNS depressant is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Temazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as tolcapone, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how tetrabenazine affects them.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as tolcapone due to the potential for additive sedative effects.
    Thiethylperazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Thioridazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Thiothixene: (Major) Thiothixene may inhibit the clinical antiparkinsonian response to COMT inhibitors like entacapone and tolcapone by blocking dopamine receptors in the brain. In addition, COMT inhibitors and thiothixene should be given together cautiously due to the possibility of additive sedation. In general, avoid thiothixene in patients requiring therapy for Parkinson's disease unless the benefit of the neuroleptic outweighs the risk of decreased therapeutic response to levodopa or other treatments. The use of older neuroleptics should generally not be necessary given the data indicating that parkinson's related psychosis can generally be safely and effectively treated by newer antipsychotics without a worsening of extrapyramidal symptoms.
    Tizanidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation.
    Tramadol: (Moderate) COMT inhibitors can cause CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant.
    Tranylcypromine: (Severe) At least 14 days should elapse between the discontinuation of tranylcypromine, which is a non-selective MAO inhibitor, and the use of a COMT inhibitor to avoid potential interactions. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the 2 major enzymes involved in the metabolism of catecholamines. The combination of a COMT inhibitor and tranylcypromine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism, which may lead to hypertensive crisis or other adverse effects.
    Trazodone: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Triazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Tricyclic antidepressants: (Moderate) Catechol-O-methyltransferase (COMT) inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants (TCAs), due to the possibility of additive sedation, dizziness, and other CNS depressive effects. Pharmacokinetic interactions have not been reported. No pharmacokinetic interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone. Tolcapone did not change the pharmacokinetics of desipramine in a drug interaction study.
    Trifluoperazine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including phenothiazines, due to the possibility of additive sedation. In addition, phenothiazines may inhibit the clinical antiparkinsonian response by blocking dopamine receptors in the brain.
    Warfarin: (Minor) Although evidence for an interaction is lacking, the affinity of tolcapone for CYP2C9 may result in enhanced anticoagulation with warfarin, a substrate for CYP2C9. Clinical studies with sensitive CYP2C9 substrates did not indicate a major effect of tolcapone on CYP2C9-induced drug metabolism. However, since data are limited regarding warfarin, the manufacturer recommends that the INR be monitored with tolcapone initation and at dose changes to ensure proper patient INR goals.
    Zaleplon: (Moderate) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Similar interactions may occur with other CNS depressants including COMT inhibitors. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as COMT inhibitors. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Zolpidem: (Moderate) COMT inhibitors such as entacapone and tolcapone should be given cautiously with other agents that cause CNS depression, including zolpidem, due to the possibility of additive sedation. Sleep-related behaviors, such as sleep-driving, are also more likely to occur during concurrent use of zolpidem and CNS depressants than with zolpidem alone. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.

    PREGNANCY AND LACTATION

    Pregnancy

    There is no experience from clinical studies regarding the use of tolcapone during human pregnancy. The low molecular weight of the drug suggests that placental transfer is likely. There have been postmarketing cases of severe hepatocellular injury with use of tolcapone, including fulminant liver failure resulting in death, and the potential risk to the developing fetus is unknown. Tolcapone is always given with levodopa/carbidopa, which has been known to cause visceral and skeletal malformations in animals. There was no evidence of teratogenicity or impaired fertility in animals during use of tolcapone alone; however, the highest dose was associated with maternal toxicity, including decreased weight gain and death. During use in rats during late gestation and throughout lactation, decreased litter size and impaired growth and learning were observed in the female offspring. Treatment in rabbits during organogenesis resulted in an increased rate of abortion and maternal toxicity. During animal studies evaluating a combination of tolcapone, levodopa, and carbidopa during organogenesis at half the expected human exposure of tolcapone and 6 times the expected levodopa human exposure, there was an increased incidence of fetal anomalies (primarily external and skeletal digit defects) compared to levodopa/carbidopa treatment without tolcapone. In rats, the three-drug combination at half the expected tolcapone human exposure or higher and 21 times the expected levodopa human exposure or greater was associated with decreased fetal body weights; however, no effect on weight was observed during use of tolcapone alone. Because human data are unavailable and animal reproduction studies are not always predictive of human response, tolcapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effects of tolcapone in labor and delivery are unknown.

    According to the manufacturer, it is unknown if tolcapone is excreted in human milk; however it is excreted into maternal milk in rats. The molecular weight of the drug suggests that excretion into human breast milk is likely. Due to the possibility that tolcapone may be excreted into human milk and the risk for serious side effects such as liver injury, the manufacturer recommends caution when tolcapone is administered to breast-feeding women. Because tolcapone is always administered with carbidopa/levodopa, breast-feeding precautions for these agents should also be followed. In addition, tolcapone enhances levodopa bioavailability, potentially exposing the nursing infant to increased levels of levodopa. If possible, tolcapone should be avoided during breast-feeding. Until more data become available, entacapone may be the preferred COMT inhibitor during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), however, the exact mechanism of inhibition is unknown. Tolcapone is not a dopamine-receptor agonist. In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT is also present in the heart, lung, smooth muscle, skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, erythrocytes, and neuronal tissues, especially glial cells. Like monoamine oxidase (MAO), COMT is responsible for the metabolism of catecholamines, however, COMT is more specific and more rapid acting than MAO. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Substrates of COMT include dopa, dopamine, norepinephrine, epinephrine, and their hydroxylated metabolites. In the presence of a decarboxylase inhibitor (e.g., carbidopa), COMT becomes the major metabolizing enzyme for levodopa which results in formation of a metabolite (3-O-methyldopa) that interferes with transport of levodopa into the CNS. This metabolite is also associated with the 'wearing-off' phenomenon. Inhibition of COMT by tolcapone and inhibition of decarboxylase by carbidopa results in more sustained plasma concentrations of levodopa (and lower 3-O-methyldopa concentrations). As a result, more levodopa is available for diffusion into the central nervous system (CNS) where it is converted to dopamine, thereby potentiating the activity of dopamine in the CNS. Cerebrospinal fluid concentrations of levodopa and total dopamine were significantly increased (88% and 92%, respectively) after 8 weeks of therapy with tolcapone and levodopa-carbidopa.

    PHARMACOKINETICS

    Tolcapone is administered orally. Tolcapone does not distribute widely into tissues due to its high plasma protein binding. The plasma protein binding is more than 99.9% (primarily to albumin) over the concentration range of 0.32 to 210 mcg/mL. Tolcapone is almost completely metabolized. The main metabolic pathway is glucuronidation to an inactive glucuronide conjugate. Tolcapone is also methylated by catechol-O-methyltransferase (COMT) to 3-O-methyl-tolcapone. In addition, tolcapone metabolism includes hydroxylation of the methyl group to form a primary alcohol, which is subsequently oxidized to the carboxylic acid possibly via CYP450 3A4 and 2A6. Reduction to an amine and subsequent N-acetylation occur to a minor extent. After oral administration of a C-labeled dose of tolcapone, 60% of labeled material was excreted in urine and 40% in feces. The glucuronide metabolite is primarily excreted in the urine but is also excreted in the bile. Approximately 0.5% of unchanged drug is eliminated in the urine. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C9, COMT
    Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. Due to its affinity to CYP2C9 in vitro, tolcapone may interfere with drugs dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely, but caution is recommended if a patient is receiving warfarin due to the limited data. In vitro experiments have found no relevant interactions with substrates for CYP2A6, CYP1A2, CYP3A4, CYP2C19 and CYP2D6. An in vivo study with desipramine confirmed an absence of an interaction with CYP2D6.

    Oral Route

    Following oral administration, tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing decreases the relative bioavailability by 10 to 20%. However, the drug may be taken with or without food.