Comtan

Anti-Parkinson Agents, COMT Inhibitors

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

Oral Administration

May administer with or without food.
Always administer with levodopa/carbidopa (either immediate or sustained release formulations).

Severe

rhabdomyolysis / Delayed / Incidence not known
neuroleptic malignant syndrome-like symptoms / Delayed / Incidence not known
ventricular tachycardia / Early / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known

Moderate

dyskinesia / Delayed / 25.0-25.0
constipation / Delayed / 6.0-6.0
orthostatic hypotension / Delayed / 4.3-4.3
dyspnea / Early / 3.0-3.0
gastritis / Delayed / 1.0-1.0
sudden sleep onset / Delayed / Incidence not known
psychosis / Early / Incidence not known
confusion / Early / Incidence not known
hallucinations / Early / Incidence not known
withdrawal / Early / Incidence not known
hypotension / Rapid / Incidence not known
colitis / Delayed / Incidence not known
impulse control symptoms / Delayed / Incidence not known

Mild

nausea / Early / 14.0-14.0
hyperkinesis / Delayed / 10.0-10.0
diarrhea / Early / 10.0-10.0
urine discoloration / Early / 10.0-10.0
dizziness / Early / 8.0-8.0
abdominal pain / Early / 8.0-8.0
fatigue / Early / 6.0-6.0
vomiting / Early / 4.0-4.0
back pain / Delayed / 2.0-4.0
xerostomia / Early / 3.0-3.0
drowsiness / Early / 2.0-2.0
anxiety / Delayed / 2.0-2.0
flatulence / Early / 2.0-2.0
dyspepsia / Early / 2.0-2.0
hyperhidrosis / Delayed / 2.0-2.0
purpura / Delayed / 2.0-2.0
asthenia / Delayed / 2.0-2.0
syncope / Early / 1.2-1.2
agitation / Early / 1.0-1.0
dysgeusia / Early / 1.0-1.0
infection / Delayed / 1.0-1.0
myalgia / Early / Incidence not known
tongue discoloration / Delayed / Incidence not known
skin discoloration / Delayed / Incidence not known

Comtan

Rx

Reversible peripheral COMT inhibitor; improves levodopa availability in the CNS
Used for adults with Parkinson's disease as an adjunct to levodopa/carbidopa
Increased levodopa-induced side effects may be seen during initial therapy; shorter COMT inhibition but improved side effect profile compared to tolcapone

For use as an adjunct to levodopa and carbidopa to treat end-of-dose 'wearing-off' in patients with Parkinson's disease. Oral dosage Adults

200 mg PO administered with each levodopa/carbidopa dose, up to a maximum of 8 times per day. Most patients in clinical trials received 200 mg PO 4 to 6 times per day. To optimize response, reductions in the daily levodopa dosage or extending the interval levodopa dosage may be necessary. Max: 1,600 mg/day PO. There is limited experience with doses more than 1,600 mg/day. In clinical trials, the majority of patients receiving levodopa (800 mg/day or more) or who had moderate or severe levodopa-induced dyskinesias before beginning entacapone treatment required a decrease of about 25% in their daily levodopa dosage. DISCONTINUATION: If a decision is made to discontinue entacapone therapy, patients should be monitored closely, and other dopaminergic treatments should be adjusted as needed. Although tapering of entacapone has not been systemically evaluated, it would be prudent to withdraw patients slowly if treatment is to be discontinued.

Hepatic Impairment

Use with caution in patients with hepatic impairment; carefully adjust dosage to clinical response. Specific dosage adjustment guidelines are not available.

Renal Impairment

No dosage adjustments are required; only 0.2% of a dose is excreted unchanged in the urine.

Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Alfentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with alfentanil. Monitor patients receiving alfentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
Alprazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Amoxapine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Ampicillin: (Moderate) As entacapone is primarily excreted in the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidation, such as ampicillin, are given concurrently with entacapone.
Ampicillin; Sulbactam: (Moderate) As entacapone is primarily excreted in the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidation, such as ampicillin, are given concurrently with entacapone.
Articaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Atropine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Atropine; Difenoxin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
atypical antipsychotic: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including COMT inhibitors. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Barbiturates: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Belladonna; Opium: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with COMT inhibitors, such as entacapone, may cause additive sedation and somnolence. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Benzodiazepines: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Bupivacaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sodium oxybate, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and entacapone. CNS depressants can potentiate the effects of cannabidiol.
Celecoxib; Tramadol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Cetirizine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cetirizine; Pseudoephedrine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chloramphenicol: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidation such as chloramphenicol. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Chlordiazepoxide: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlordiazepoxide; Clidinium: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Chlorpromazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Chlorthalidone; Clonidine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including clonidine, due to the possibility of additive sedation and hypotension. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cholestyramine: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation, or intestinal beta-glucuronidation such as cholestyramine. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Clobazam: (Moderate) An enhanced CNS depressant effect may occur when clobazam is combined with entacapone, a COMT inhibitor. Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. COMT inhibitors may cause drowsiness and have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clonazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clonidine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including clonidine, due to the possibility of additive sedation and hypotension. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Clorazepate: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Codeine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as entacapone, 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.
Dexmedetomidine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including dexmedetomidine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Monitor patients closely for additive effects that may prolong recovery from dexmedetomidine administration.
Diazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diphenoxylate; Atropine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Dobutamine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase (COMT), such as dobutamine, should be administered cautiously to patients receiving COMT inhibitors. 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 (COMT), such as dopamine, should be administered cautiously to patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Dronabinol: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including dronabinol, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Droperidol: (Major) Use droperidol with caution in patients taking COMT inhibitors due to the possibility of additive sedation. Droperidol produces marked tranquilization and sedation; reduced dosages may be needed in debilitated patients, particularly when combined with other CNS depressants.
Ephedrine: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as ephedrine or ephedra, ma huang should be administered cautiously in patients receiving entacapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Ephedrine; Guaifenesin: (Major) Drugs known to be metabolized by catechol-O-methyltransferase, such as ephedrine or ephedra, ma huang should be administered cautiously in patients receiving entacapone. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Erythromycin: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as erythromycin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Esketamine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as entacapone, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Estazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Eszopiclone: (Major) 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 from eszopiclone may be increased during coadministration, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Etomidate: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Fentanyl: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Flibanserin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including flibanserin, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Fluphenazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Flurazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and entacapone. Concomitant use of gabapentin with entacapone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
General anesthetics: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Guanfacine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including guanfacine, due to the possibility of additive sedation or hypotension. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Haloperidol: (Major) Due to opposing effects on central dopaminergic activity, haloperidol and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to haloperidol. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Heterocyclic antidepressants: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as methyldopa, 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. Additive sedation and hypotension can occur. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Hydrocodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Hydromorphone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Isocarboxazid: (Contraindicated) 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.
Isoflurane: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Isoniazid, INH: (Major) Patients should generally not receive COMT inhibitors in combination with agents that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a 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 that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a 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. (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Isoniazid, INH; Rifampin: (Major) Patients should generally not receive COMT inhibitors in combination with agents that have some non-selective MAO inhibiting activity like isoniazid. It is recommended that at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a 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. (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Isoproterenol: (Moderate) 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.
Ketamine: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and entacapone. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as entacapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and entacapone. Dosage adjustments of lemborexant and entacapone may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Levocetirizine: (Moderate) Caution is recommended during concurrent use of cetirizine or levocetirizine with COMT inhibitors because of the possibility for additive sedative effects. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Levorphanol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Lidocaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Linezolid: (Major) Avoid the concomitant use of COMT inhibitors in combination with linezoid, which has non-selective monoamine oxidase (MAO) inhibitor activity. Typically, at least 14 days should elapse between the discontinuation of a non-selective MAOI and the use of a COMT inhibitor to avoid potential interactions. Consider an alternative to linezolid if possible. Monoamine oxidase and catechol-O-methyltransferase (COMT) are the two major enzymes involved in the metabolism of catecholamines. It is theoretically possible that the coadministration of a COMT inhibitor with linezolid would result in inhibition of normal catecholamine metabolism and possible toxicity.
Lofexidine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and entacapone. Lofexidine can potentiate the effects of CNS depressants.
Lorazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Loxapine: (Major) Due to opposing effects on central dopaminergic activity, loxapine and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider if an atypical antipsychotic is a potential alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Maprotiline: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Melatonin: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including melatonin, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Meperidine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Meprobamate: (Moderate) Additive CNS depressant effects are possib

le during coadministration of COMT inhibitors and meprobamate. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Methadone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Methyldopa: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as methyldopa, 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. Additive sedation and hypotension can occur. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Methylphenidate Derivatives: (Minor) Due to their pharmacologic actions, it is thought that increased dopaminergic effects may occur during coadministration of methylphenidate derivatives, inhibitors of dopamine reuptake, and COMT inhibitors. Be alert for any dopamine-related side effects such as nausea, reduced appetite, tremor, or changes in moods or behaviors.
Metoclopramide: (Moderate) Coadministration of COMT inhibitors and metoclopramide should be avoided if possible. Metoclopramide may interfere with the effectiveness of COMT inhibitors. Metoclopramide has dopamine antagonist properties while COMT inhibitors increase the availability of catecholamine concentrations (e.g., dopamine) in the central nervous system.
Midazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Mirtazapine: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Molindone: (Major) Due to opposing effects on central dopaminergic activity, molindone and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Morphine: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants like entacapone can potentiate the effects of nabilone on respiratory depression.
Nefazodone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Norepinephrine: (Moderate) Drugs known to be metabolized by catechol-O-methyltransferase, such as norepinephrine, should be administered cautiously to patients receiving COMT inhibitors. Concomitant use may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure.
Oliceridine: (Major) Concomitant use of oliceridine with entacapone may cause excessive sedation and somnolence. Limit the use of oliceridine with entacapone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Opiate Agonists-Antagonists: (Major) 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 and CNS depression.
Oxazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Oxycodone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Oxymorphone: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
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 entacapone.
Perphenazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Perphenazine; Amitriptyline: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Phenelzine: (Contraindicated) 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.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including scopolamine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including systemic atropine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Phenothiazines: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Pimozide: (Major) Due to opposing effects on central dopaminergic activity, pimozide and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic instead of pimozide if appropriate. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Pramipexole: (Moderate) Coadministration of COMT inhibitors and pramipexole may cause additive sedation. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and COMT inhibitors. Concomitant use of pregabalin with COMT inhibitors may cause additive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Prilocaine; Epinephrine: (Moderate) Use COMT inhibitors and epinephrine, regardless of route, together with caution due to potential for increased heart rate, arrhythmias, and excessive changes in blood pressure. Epinephrine is metabolized by catechol-O-methyltransferase (COMT), therefore COMT inhibitors potentiate the pressor effects of epinephrine.
Probenecid: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as probenecid. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Probenecid; Colchicine: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as probenecid. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
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) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine; Dextromethorphan: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Promethazine; Phenylephrine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Propofol: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
Quazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
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.
Ramelteon: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including ramelteon, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Remifentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with remifentanil. Monitor patients receiving remifentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
Remimazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Rifampin: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as rifampin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
Scopolamine: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including scopolamine, due to the possibility of additive sedation. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Sedating H1-blockers: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Sevoflurane: (Major) Additive CNS depression and hypotension may occur when general anesthetics and COMT inhibitors are used together. Monitor patients closely for additive effects that may prolong recovery.
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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Sodium Oxybate: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sodium oxybate, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as entacapone. Caution is recommended since this combination has not been evaluated.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and entacapone. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) COMT inhibitors may cause additive sedation or hypotension with sufentanil. Monitor patients receiving sufentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
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: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tasimelteon: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tasimelteon, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Temazepam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as entacapone, 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) The use of thalidomide and COMT inhibitors may cause an additive sedative effect and should be avoided if possible. If concurrent treatment is needed, prescribers should monitor patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Thioridazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Thiothixene: (Major) Due to opposing effects on central dopaminergic activity, thiothixene and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to thiothixene. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tramadol: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Tranylcypromine: (Contraindicated) 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: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as trazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Triazolam: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tricyclic antidepressants: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Trifluoperazine: (Major) Due to opposing effects on central dopaminergic activity, phenothiazines and COMT inhibitors may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Valerian, Valeriana officinalis: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valerian, due to the possibility of additive sedation.
Valproic Acid, Divalproex Sodium: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including valproic acid, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Warfarin: (Moderate) Monitoring of the INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Entacapone has affinity for CYP2C9. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (Cl 90 11% to 26%), and the INR values increased on average by 13% (Cl 90 6% to 19%).
Zaleplon: (Major) Additive CNS depressant effects are possible during concurrent use of COMT inhibitors and zaleplon. If concurrent use is necessary, monitor for additive side effects. A reduction in the dose of one or both drugs may be needed. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Zolpidem: (Major) 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. 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.

Comtan/Entacapone Oral Tab: 200mg

Adults

1,600 mg/day PO. Limited data are available for doses more than 1,600 mg/day.

Geriatric

1,600 mg/day PO. Limited data are available for doses more than 1,600 mg/day.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Not indicated.

Entacapone is a reversible, selective inhibitor of peripheral catechol-O-methyltransferase (COMT). COMT acts to eliminate biologically active catechols and their metabolites. COMT catalyzes the transfer of the methyl group of S-adenyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Substrates of COMT include dopa and catecholamines (dopamine, epinephrine, and norepinephrine) and their hydroxylated metabolites. COMT is distributed throughout various organs with the highest level of activity in the liver and kidney. Other organs that contain COMT are the heart, lung, smooth and skeletal muscle, intestinal tract, reproductive organs, adipose tissue, various glands, skin, blood cells, and neuronal tissues, especially glial cells. Following 200 mg of entacapone, erythrocyte COMT activity is inhibited roughly 65% and returns to baseline within 8 hours. In the presence of a decarboxylase inhibitor (e.g., carbidopa), COMT becomes the major metabolizing enzyme for levodopa, which results in formation of a levodopa metabolite (3-O-methyldopa) that has been associated with reduced efficacy of levodopa, the 'wearing-off' phenomenon, and dyskinesia. Entacapone should always be administered in association with levodopa and carbidopa. Entacapone has no antiparkinsonian effect of its own. Inhibition of COMT by entacapone and inhibition of decarboxylase by carbidopa results in more sustained plasma concentrations of levodopa and markedly lower 3-O-methyldopa concentrations. As a result, more levodopa is available for diffusion into the CNS where it is converted to dopamine, thereby potentiating the activity of dopamine in the CNS. When entacapone is given with levodopa and carbidopa, the AUC of levodopa is increased by approximately 35% and the elimination half-life of levodopa is increased from 1.3 hours to 2.4 hours. In general, levodopa peak plasma levels and time to peak plasma levels are unaffected. The higher AUC and duration of action may lead to increased levodopa adverse effects, sometimes requiring a reduction in the levodopa dosage.

Entacapone is administered orally and exhibits linear pharmacokinetics that are independent of levodopa/carbidopa coadministration. It is 98% protein bound to albumin primarily and, therefore, is not widely distributed into tissues. Metabolism is extensive and occurs through isomerization to the cis-isomer, followed by direct glucuronidation of both the parent and cis-isomer. The glucuronide metabolites are inactive. Only a very small amount (0.2% of the dose) is found unchanged in the urine. After oral administration, 10% of the dose is excreted in the urine and 90% in the feces via biliary excretion. The elimination half-life is 1 to 2 hours following a 200 mg dose, which is similar to the half-life of levodopa.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: COMT, CYP2C9
Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT) and may influence the pharmacokinetics of drugs metabolized by COMT. Entacapone has also been reported to increase the exposure of warfarin (a CYP2C9 substrate). In vitro studies have shown that entacapone can inhibit CYP1A2, CYP2A6, CYP2C6, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, but only at very high concentrations (IC50 more than 200 microM) that would not be seen with normal clinical use. A 200 mg dose in adults usually produces a concentration of 5 microM.

Oral Route

Entacapone is rapidly absorbed after oral administration with an absolute bioavailability of 35%. The mean peak concentration (Cmax) of 1160 to 1500 mcg/L is attained approximately 1 hour following a 200 mg dose. Food does not affect the pharmacokinetics of entacapone.

Pregnancy

There is no experience from clinical studies regarding the use of entacapone during human pregnancy. The low molecular weight of the drug suggests that placental transfer is likely. Because human data are too limited to be conclusive and animal reproduction studies are not always predictive of human response, entacapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Entacapone is always given concomitantly with levodopa/carbidopa, which has been known to cause visceral and skeletal malformations in animals. During animal studies, when entacapone was given to rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies was noted at high doses (plasma AUCs 7-times those in humans receiving the maximum daily dose). Entacapone has not shown to be teratogenic effects in rabbits. Entacapone did not result in impaired fertility or general reproductive performance in animals; however, delayed mating occurred at the highest dose. A case of neonatal seizure occurred after use of bromocriptine plus carbidopa/levodopa/entacapone in a pregnant woman. The effects of entacapone in labor and delivery are unknown.

According to the manufacturer, it is unknown if entacapone 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. Because of the possibility that entacapone may be excreted into human milk, the manufacturer recommends caution when entacapone is administered to breast-feeding women. Since entacapone is always administered with carbidopa/levodopa, breast-feeding precautions for these agents should also be followed, as levodopa is excreted in human milk. If treatment with entacapone cannot be avoided during breast-feeding, the infant should be monitored for commonly encountered adverse effects of COMT inhibitor therapy including nausea, sedation, and diarrhea. One published study suggests that nursing or pumping milk at times of lower levodopa breast milk levels may help minimize the amount of levodopa received by an infant. 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.