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  • CLASSES

    Anti-Parkinson drugs, COMT Inhibitors

    BOXED WARNING

    Hepatic disease, hepatotoxicity

    Tolcapone is contraindicated in patients with hepatic disease or in patients previously withdrawn from tolcapone due to evidence of tolcapone-induced hepatocellular injury.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 with moderate non-cirrhotic liver disease have reduced clearance of unbound tolcapone by almost 50%, increasing the average concentration of unbound drug by about two-fold. Further, some patients (1—3%) treated with tolcapone develop elevated hepatic enzymes. Cases of severe hepatocellular injury, including cases of fatal hepatic failure resulting in death, have been reported in post-marketing use of tolcapone. It is recommended that liver enzymes (i.e., ALT/AST) be monitored at baseline and then periodically (i.e., every 2 to 4 weeks) for the first 6 months while on tolcapone therapy. After the first 6 months, periodic liver enzyme monitoring is recommended at intervals deemed clinically relevant. Upward dose adjustments may require additional liver enzyme monitoring. Patients who fail to show substantial clinical benefit within the first 3 weeks of tolcapone therapy should be withdrawn from the medication due to the risk of severe hepatic toxicity with continued treatment. Tolcapone should be discontinued for hepatic enzyme elevations greater than 2 times the upper limit of normal (ULN) or at the appearance of signs or symptoms of the onset of hepatic dysfunction or failure. Patients receiving tolcapone should be advised to report symptoms of potential liver injury, such as fatigue, abdominal pain (upper right quadrant tenderness), clay-colored stools, persistent nausea, loss of appetite, dark urine, pruritus or jaundice to their health care professional for evaluation.

    DEA CLASS

    Rx

    DESCRIPTION

    Peripheral and centrally acting oral COMT inhibitor; more potent than entacapone but less tolerable side effect profile; improves levodopa availability and duration in the CNS; increased levodopa-induced side effects may be seen during initial therapy; Black Box warning exists in labeling for fulminant hepatic 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.
    NOTE: Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or 2 separate liver enzyme values greater than the upper limit of normal. Tolcapone should be discontinued if liver enzymes exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest hepatic dysfunction. Patients must provide written and informed consent prior to beginning therapy with tolcapone.
    Oral dosage
    Adults

    Initially 100 mg PO three times per day, to limit the potential for increased dopamine-related effects (e.g., dyskinesias) and the possible need to decrease the concomitant levodopa/carbidopa dose. 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 three times per day unless the incremental clinical benefit is likely to exceed the potential increased risk of hepatotoxicity. If the dose is increased to 200 mg PO three times a day, liver enzyme monitoring should take place before increasing the dose and then every 2—4 weeks for the next 6 months. After 6 months, periodic monitoring is recommended at intervals deemed clinically relevant. The maximum recommend dose is 600 mg/day PO, given in three divided doses. If there is no clinical benefit on any dose after a total of 3 weeks of treatment, tolcapone should be discontinued.

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Elderly

    600 mg/day PO.

    Adolescents

    Safety and efficacy have not been established. 

    Children

    Safety and efficacy have not been established. 

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Because of the risk of hepatic injury, patients with clinical evidence of liver disease or elevated hepatic enzymes values (ALT and/or AST) that are above the upper limits of normal (ULN) on 2 occasions should not receive tolcapone. Tolcapone should be discontinued if liver enzymes exceed 2 times ULN or if clinical signs and symptoms suggest hepatic dysfunction.

    Renal Impairment

    CrCl >= 25 ml/min: Per the manufacturer, no dose adjustment is recommended for patients with mild to moderate renal impairment.
    CrCl < 25 ml/min: 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.

    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. 
     
    Tolcapone may potentiate the dopaminergic adverse effects of levodopa and may cause and/or exacerbate preexisting 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. Rare cases of a symptom complex resembling neuroleptic malignant syndrome have been observed in clinical trials and during post-marketing use, and have been associated with abrupt withdrawal or dose reduction of tolcapone. Symptoms have included hyperpyrexia, confusion, muscle rigidity, altered consciousness, and elevated CPK. Causality to tolcapone has not been established.

    Hepatic disease, hepatotoxicity

    Tolcapone is contraindicated in patients with hepatic disease or in patients previously withdrawn from tolcapone due to evidence of tolcapone-induced 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 with moderate non-cirrhotic liver disease have reduced clearance of unbound tolcapone by almost 50%, increasing the average concentration of unbound drug by about two-fold. Further, some patients (1—3%) treated with tolcapone develop elevated hepatic enzymes. Cases of severe hepatocellular injury, including cases of fatal hepatic failure resulting in death, have been reported in post-marketing use of tolcapone. It is recommended that liver enzymes (i.e., ALT/AST) be monitored at baseline and then periodically (i.e., every 2 to 4 weeks) for the first 6 months while on tolcapone therapy. After the first 6 months, periodic liver enzyme monitoring is recommended at intervals deemed clinically relevant. Upward dose adjustments may require additional liver enzyme monitoring. 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. Tolcapone should be discontinued for hepatic enzyme elevations greater than 2 times the upper limit of normal (ULN) or at the appearance of signs or symptoms of the onset of hepatic dysfunction or failure. Patients receiving tolcapone should be advised to report symptoms of potential liver injury, such as fatigue, abdominal pain (upper right quadrant tenderness), clay-colored stools, persistent nausea, loss of appetite, dark urine, pruritus or jaundice to their health care professional for evaluation.

    Hypotension, syncope

    Tolcapone should be used cautiously in patients with hypotension or 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.

    Anorexia nervosa, diarrhea

    Tolcapone should be used cautiously in patients with preexisting diarrhea. Diarrhea was the most common adverse reaction leading to discontinuation of tolcapone therapy. Severe diarrhea developed in 3—4% of patients receiving tolcapone. Tolcapone-induced diarrhea may sometimes be associated with anorexia, therefore, use cautiously in patients with anorexia nervosa.

    Renal disease, renal impairment

    Tolcapone should be used cautiously in patients with severe renal impairment or renal disease. Tolcapone use has not been examined in patients with severe renal impairment or disease. No dosage adjustment is needed in patients with mild to moderate renal impairment.

    Hematuria

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

    Pregnancy

    Tolcapone is classified as FDA pregnancy category C. There is no experience from clinical studies regarding the use of tolcapone in pregnant women. The low molecular weight of the drug suggests that placental transfer is likely. There have been post-marketing 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.

    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, 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. There have been post-marketing cases of severe hepatocellular injury from tolcapone, including fulminant liver failure resulting in death, and the potential risk to the nursing infant is unknown. 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.

    Children

    Safe and effective use of tolcapone has not been established in children. There is no identified potential use of tolcapone in pediatric patients.

    Driving or operating machinery

    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. 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, use of concomitant CNS depressant medications, or 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.

    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.

    Impulse control symptoms

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense 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. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving tolcapone. Likewise, patients should be instructed to report such changes while receiving tolcapone. Dose reduction or discontinuation should be considered in those who experience these effects.

    Abrupt discontinuation

    Abrupt discontinuation of tolcapone should be avoided if possible. Withdrawal of tolcapone therapy should proceed slowly. Closely monitor patients and adjust other dopaminergic treatments as necessary. Adverse events resembling neuroleptic malignant syndrome have been reported in association with rapid dose reduction or withdrawal of tolcapone (see Adverse Reactions).

    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.

    Psychosis

    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.

    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
    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 (unspecified) / 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: (Major) Patients should not receive a COMT inhibitor in combination with non-selective MAOIs such as isocarboxazid. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes involved in the metabolism of catecholamines and the combination of a COMT inhibitor and isocarboxazid may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of isocarboxazid and the use of a COMT inhibitor to avoid potential interactions.
    Isoniazid, INH: (Major) Patients should not receive COMT-inhibitors like entacapone or tolcapone in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. Monoamine oxidase and catechol-O-methyltransferase are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the combination of entacapone or tolcapone and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of the non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Patients should not receive COMT-inhibitors like entacapone or tolcapone in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. Monoamine oxidase and catechol-O-methyltransferase are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the combination of entacapone or tolcapone and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of the non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions.
    Isoniazid, INH; Rifampin: (Major) Patients should not receive COMT-inhibitors like entacapone or tolcapone in combination with agents with non-selective MAO inhibiting activity like isoniazid, INH. Monoamine oxidase and catechol-O-methyltransferase are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the combination of entacapone or tolcapone and a non-selective MAOI would result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of the non-selective MAOI and the use of the COMT-inhibitor to avoid potential interactions.
    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: (Major) Patients should not receive a COMT inhibitor in combination with non-selective MAOIs such as phenelzine. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes involved in the metabolism of catecholamines and the combination of a COMT inhibitor and phenelzine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of phenelzine and the use of a COMT inhibitor to avoid potential interactions.
    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) Patients should not receive COMT-inhibitors in combination with agents with non-selective MAO inhibiting activity like procarbazine. MAO and COMT are the two 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. 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.
    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: (Major) Patients should not receive a COMT inhibitor in combination with non-selective MAOIs such as tranylcypromine. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes involved in the metabolism of catecholamines and the combination of a COMT inhibitor and tranylcypromine may result in inhibition of the majority of pathways responsible for normal catecholamine metabolism. Typically, at least 14-days should elapse between the discontinuation of tranylcypromine and the use of a COMT inhibitor to avoid potential interactions.
    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: (Moderate) In an interaction study, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (90% CI, 11-26%), and the INR values increased on average by 13% (90% CI 6-19%). Nevertheless, cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postmarketing period of entacapone. Therefore, monitoring of INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin.
    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

    Tolcapone is classified as FDA pregnancy category C. There is no experience from clinical studies regarding the use of tolcapone in pregnant women. The low molecular weight of the drug suggests that placental transfer is likely. There have been post-marketing 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, 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. There have been post-marketing cases of severe hepatocellular injury from tolcapone, including fulminant liver failure resulting in death, and the potential risk to the nursing infant is unknown. 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

    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 >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 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 cytochrome P450 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—3 hours and there is no significant accumulation.

    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—20%.