AHFS Class:

• Catechol-O-Methyltransferase (COMT) Inhibitors 28:36.12

Generic Name(s):

• Opicapone

Chemical Name:

• 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxidopyridin-1-ium-3-yl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol

Molecular Formula:

• C₁₅H₁₀Cl₂N₄O₆

Opicapone is a selective and reversible catechol- O -methyltransferase (COMT) inhibitor.1,3 Concomitant administration of opicapone with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased and more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1,2

Parkinsonian Syndrome

Opicapone is used as adjunctive treatment to levodopa/carbidopa in patients with parkinson disease experiencing “off” episodes.1,4,8

Levodopa is currently the most effective drug available for relieving the motor symptoms of parkinson disease and has traditionally been considered the drug of choice for this use.115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a COMT inhibitor.101,115,116,123,157 Adjunctive therapy with a COMT inhibitor prolongs the duration of action of levodopa and reduces peak-trough variations through inhibition of its metabolism.3,4 The appropriate treatment approach should be individualized based on the patient's age, symptoms, degree of disability, and adverse effects of therapy.101,120,122,123,124,125 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Other drugs in the COMT inhibitor class include entacapone and tolcapone.3 A major difference between opicapone and these other COMT inhibitors is the duration of action.2 While the duration of action of opicapone permits once-daily administration, the short durations of tolcapone and entacapone require multiple daily doses.2 Due to the risk of potentially fatal hepatotoxicity, tolcapone is generally reserved for patients who are nonresponsive to or intolerant of other adjunctive antiparkinsonian agents.4,5 Opicapone has been shown to be noninferior to entacapone when used as adjunctive treatment to levodopa/carbidopa in patients with advanced parkinson disease experiencing motor fluctuations, and may offer some benefit due to its once-daily dosing and fewer GI adverse effects.4,6,7

Efficacy of opicapone as an adjunct to levodopa/carbidopa in reducing “off” episodes in patients with parkinson disease was established in 2 phase 3 studies of similar design (Bipark-1 and Bipark-2).1,4,8 Both trials were randomized, double-blind, controlled, multicenter, international trials conducted in patients with advanced parkinson disease (mean disease duration of 7-8.2 years) who had signs of end-of-dose deterioration while receiving levodopa in combination with a decarboxylase inhibitor (alone or in addition to other antiparkinsonian agents such as a dopamine agonist, amantadine, monoamine oxidase-B [MAO-B] inhibitor, or anticholinergic agent).4,8 The primary outcome of both studies was change in mean absolute “off” time based on 24-hour patient diaries.1,4,8

Bipark-1 included 600 patients who were randomized to placebo, entacapone 200 mg (administered with each levodopa dose), opicapone 5 mg daily, opicapone 25 mg daily, or opicapone 50 mg daily.1 Compared with placebo, the mean absolute “off” time was substantially decreased in those treated with opicapone 50 mg daily (decrease of 1.01 hours).1 The adjusted least-squares mean decrease from baseline in absolute “off” time over the duration of the trial (14-15 weeks) was 116.8 minutes with opicapone 50 mg daily.4 The 50-mg dosage of opicapone was superior to placebo and noninferior to entacapone.1,4 No significant differences in “off” time were observed between the lower opicapone dosages evaluated and placebo.4

Bipark-2 included 427 patients who were randomized to opicapone 25 mg daily, opicapone 50 mg daily, or placebo.1 Compared with placebo, mean absolute “off” time was substantially decreased in those treated with opicapone 50 mg daily (decrease of 0.91 hours).1 The adjusted least-squares mean decrease from baseline in “off” time over the duration of the trial (14-15 weeks) was 118.8 minutes with opicapone 50 mg daily.8 No significant differences were observed between the lower opicapone dosage evaluated and placebo.1,8

The reduction in “off” time observed with opicapone in the Bipark-1 and Bipark-2 studies was accompanied by an increase in “on” time without troublesome dyskinesia.4,8,9

Long-term efficacy results are available as pooled data from 758 patients who completed the double-blind portion of Bipark-1 and Bipark-2 and then completed 1-year open-label extensions of these pivotal trials.9 All patients entering the open-label extension received a dosage of opicapone 25 mg daily initially with the option to increase to 50 mg daily if needed and tolerated.9 Over half (54%) of the patients increased to the 50-mg daily dosage.9 Patients who were previously receiving placebo in the double-blind portion of the studies had an additional mean reduction of 51.1 minutes in absolute “off” time from the open-label baseline.9 Patients who previously received opicapone 25 mg had an additional 19.4-minute decrease, and patients who previously received opicapone 50 mg had an additional 8.2-minute decrease from open-label baseline suggesting that the clinical effects of opicapone were maintained over 1 year.9

The open-label, single-arm OPTIPARK study assessed real-world effectiveness of opicapone 50 mg daily (using parkinson disease rating scales rather than change in “off” times to assess response) in 495 patients.10 Results of this study were consistent with the pivotal trials showing significant improvement with opicapone 50 mg daily in treating motor fluctuations associated with parkinson disease.10

Data from the open-label extension of Bipark-1 also provide information on switching patients from entacapone to opicapone.11 A subset of patients who received entacapone during the double-blind phase of Bipark-1 were switched to opicapone 25 mg daily in the open-label extension and had the option to increase to opicapone 50 mg daily if needed.11 These patients experienced an additional decrease in mean “off” time of about 39.3 minutes after switching to opicapone.11

Administration

Opicapone is administered orally once daily at bedtime.1

Because presence of food in the GI tract may decrease exposure of opicapone, patients should not consume any food for 1 hour before and for at least 1 hour after taking the drug.1 (See Description.)

If a dose of opicapone is missed, the next dose should be taken at the usually scheduled time the next day.1

Dosage

Parkinsonian Syndrome

For the management of parkinson disease, opicapone is given in conjunction with levodopa/carbidopa.1,4,8 Levodopa dosage adjustments may be necessary based on clinical response (e.g., presence of dyskinesias).1,4,8

The recommended adult dosage of opicapone in patients with parkinson disease is 50 mg orally once daily at bedtime.1

In clinical studies evaluating opicapone 50 mg daily, the average daily dosage of levodopa was 700 mg.4,8 During the first 3-4 weeks of opicapone treatment, reductions in levodopa dosage were permitted according to clinical response.4,8 The mean decrease in daily levodopa dosage was 29.3-31.6 mg.4,8

Discontinuance of Opicapone Therapy

If opicapone therapy is discontinued, the patient should be closely monitored and adjustments of other dopaminergic therapies should be considered.1 Although patients in the pivotal trials discontinued opicapone without tapering or gradual withdrawal,1 tapering opicapone dosage prior to discontinuing the drug has been recommended.6 (See Withdrawal-Emergent Hyperpyrexia and Confusion under Cautions.)

Switching From Entacapone to Opicapone

The manufacturer does not make any specific recommendations for transitioning patients from entacapone to opicapone.1

In the 1-year open-label extension of the Bipark-1 study, patients were permitted to switch from entacapone (200 mg with each levodopa/carbidopa dose) to opicapone.11 The day following the end of the double-blind phase, patients who were receiving entacapone switched to opicapone 25 mg once daily at bedtime for 1 week, followed by individually tailored adjustments to levodopa and/or opicapone dosage as needed.11

Special Populations

Hepatic Impairment

The manufacturer states that no dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).1 In patients with moderate hepatic impairment (Child-Pugh class B), dosage of opicapone should be reduced to 25 mg once daily at bedtime.1 Opicapone should not be used in patients with severe hepatic impairment (Child-Pugh class C).1,6 (See Hepatic Impairment under Cautions.)

Renal Impairment

The manufacturer states that no dosage adjustment is required in patients with mild, moderate, or severe renal impairment.1 However, because of the possibility of increased exposure, which may increase the risk of adverse effects, patients with severe renal impairment should be monitored and opicapone should be discontinued if the patient is unable to tolerate the drug.1 Opicapone should be avoided in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1 (See Renal Impairment under Cautions.)

Geriatric Patients

The manufacturer states that dosage adjustment is not necessary in geriatric patients.1

Contraindications

• Concomitant use of nonselective monoamine oxidase (MAO) inhibitors.1 (See MAO Inhibitors under Drug Interactions.)
• History of pheochromocytoma, paraganglioma, or other catecholamine-secreting neoplasms.1

Warnings/Precautions

Concomitant Use with Drugs Metabolized by COMT

Concomitant use of opicapone with drugs metabolized by COMT (e.g., dobutamine, dopamine, epinephrine, isoproterenol, norepinephrine) may result in arrhythmias, increased heart rate, and excessive changes in blood pressure regardless of the route of administration (including inhalation).1 Patients receiving such concomitant therapy should be monitored for these effects.1 (See Drugs Metabolized by COMT under Drug Interactions.)

Falling Asleep During Daily Activities and Somnolence

Use of dopaminergic drugs and drugs that increase levodopa exposure (e.g., opicapone) has been associated with reports of patients falling asleep during daily activities with no preceding warning sign such as drowsiness.1 These reports include sleeping while operating a motor vehicle, which sometimes has resulted in accidents.1 The incidence of sleep attacks and somnolence was not different between opicapone and placebo in the pivotal trials.6

Prior to initiating opicapone therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, driving a motor vehicle), consideration should be given to adjusting other dopaminergic or sedating drugs, or discontinuing opicapone.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1

Hypotension and Syncope

Hypotension (both orthostatic and non-orthostatic), syncope, and presyncope were reported more frequently with opicapone 50 mg daily (5%) compared with placebo (1%) in the pivotal trials.1 Patients should be advised about these risks and monitored for hypotension during therapy with opicapone.1 If these adverse effects occur, consideration should be given to adjusting the dosages of other drugs that can lower blood pressure or discontinuing opicapone.1

Dyskinesia

Opicapone may potentiate the adverse dopaminergic effects of levodopa and may cause or exacerbate dyskinesia.1 Dyskinesia was more commonly reported with opicapone 50 mg daily (20%) compared with placebo (6%) in the pivotal trials and was the most common adverse effect leading to discontinuance of opicapone therapy.1 Reductions in the levodopa daily dosage or dosage of other dopaminergic drugs may be necessary to manage dyskinesia that occurs during treatment with opicapone.1

Hallucinations and Psychosis

Hallucinations and other neuropsychiatric symptoms are established features of advanced parkinson disease.6 However, hallucinations (including auditory, visual, and mixed hallucinations) occurred more commonly with opicapone 50 mg daily (3%) compared with placebo (1%) in the pivotal trials.1 Aggression, agitation, or delusions were reported in 1% of opicapone patients compared with no placebo patients.1

Clinicians should consider discontinuing opicapone if hallucinations or other psychotic-like behaviors occur.1 Opicapone should generally not be used in patients with major psychotic disorders due to the risk of exacerbating psychoses as a result of increased central dopaminergic tone.1 In addition, concomitant use of opicapone with certain antipsychotic agents may exacerbate parkinsonian symptoms.1

Impulse Control and Compulsive Disorders

Impulse control disorders are an established feature of advanced parkinson disease.6 These can manifest as intense urges to gamble, spend money, binge eat, or increased sexual urges.1 Patients receiving opicapone or other dopaminergic drugs have reported these urges; in some cases, the urges ceased when the dosage of opicapone was decreased or the drug was discontinued.1 Impulse control disorders were reported in 1% of patients who received opicapone 50 mg daily compared with no patients who received placebo in the pivotal trials.1,6

Clinicians should specifically ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving opicapone.1 Patients who develop impulse control disorders should have their existing parkinson disease therapies reassessed, and discontinuance of opicapone should be considered.1 Opicapone should be used with caution in patients with suspected or confirmed dopamine dysregulation syndrome.1

Withdrawal-Emergent Hyperpyrexia and Confusion

Patients undergoing rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone can develop a symptom complex resembling neuroleptic malignant syndrome (e.g., elevated temperature, muscle rigidity, altered consciousness, autonomic instability) with no other apparent etiology.1

Patients in the pivotal trials discontinued opicapone without tapering or gradual withdrawal.1 There were no reports of neuroleptic malignant syndrome in these trials.1 However, some clinicians recommend tapering opicapone when discontinuing therapy.6

Patients should be monitored, and adjustment of other dopaminergic therapies should be considered if needed.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risk associated with use of opicapone in pregnant women.1 However, there is a possibility of fetal risk based on animal studies.1 Animal data showed some evidence of adverse embryofetal development at clinically relevant plasma concentrations.1 Structural abnormalities were seen when opicapone was administered to pregnant rabbits during organogenesis.1

Lactation

It is not known whether opicapone distributes into human milk or whether the drug has any effects on the breast-fed infant or on milk production.1 Opicapone distributes into milk in rats at concentrations similar to those in maternal plasma.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for opicapone, and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition .1

Pediatric Use

The safety and efficacy of opicapone have not been established in pediatric patients.1

Geriatric Use

Among patients who received opicapone 50 mg daily in the principal efficacy studies, 52% were 65 years of age and older.1 No overall differences in safety or efficacy were identified between these geriatric patients and younger patients, but increased sensitivity in some older individuals cannot be ruled out.1 A subgroup analysis of these studies found that rates of hallucinations and weight loss were more common in patients 70 years of age and older compared with younger patients.12

Hepatic Impairment

Opicapone exposure is increased in patients with hepatic impairment.1

In pharmacokinetic studies, peak plasma concentrations and AUC of opicapone increased by 34 and 35%, respectively, in patients with mild (Child-Pugh class A) hepatic impairment, which is not expected to be clinically important.1 Peak plasma concentrations and AUC of opicapone increased by 89 and 84%, respectively, in patients with moderate (Child-Pugh class B) hepatic impairment.1,6 Opicapone dosage adjustment is recommended in patients with moderate hepatic impairment, but is not needed in patients with mild hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Pharmacokinetic data are not available for patients with severe (Child-Pugh class C) hepatic impairment.1,6 Opicapone should not be used in such patients.1,6

Renal Impairment

Renal elimination has a minor role in the clearance of opicapone.1 Population pharmacokinetic analysis found no clinically important changes in the pharmacokinetics of opicapone in patients with mild or moderate (creatinine clearance 30-89 mL/minute) renal impairment.6 However, due to the potential for increased opicapone exposure, patients with severe renal impairment (creatinine clearance 15-30 mL/minute) should be monitored for adverse effects and should discontinue opicapone if needed.1 Opicapone should not be used in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Adverse effects reported in 4% or more of patients receiving opicapone in clinical studies and at a frequency greater than placebo include dyskinesia, constipation, increased blood creatine kinase, hypotension/syncope, and weight loss.1,4,8

Opicapone does not inhibit nor induce major cytochrome P-450 (CYP) isoenzymes.1

Opicapone is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, and organic anion transport proteins (OATP) 1B3 and OATP2B1.1 The drug does not inhibit P-gp, BCRP, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, OATP1B3, bile salt export pump (BSEP), multidrug and toxin extrusion transporter (MATE) 1, or MATE2-K.1

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Opicapone does not inhibit nor induce major CYP enzymes.1 Clinical studies showed that opicapone did not alter the pharmacokinetics of drugs that were CYP2C9 ( S -warfarin), CYP1A2 ( R -warfarin), CYP3A4 ( R -warfarin), or CYP2C8 (repaglinide) substrates.1

Drugs Affecting or Affected by Transport Systems

Drug interactions between opicapone and drugs affecting or affected by transport systems are not expected.1 Clinical studies showed that opicapone did not alter the pharmacokinetics of an OATP1B1 substrate (repaglinide), and the pharmacokinetics of opicapone were not altered by a P-gp substrate (quinidine).1

Acetaminophen

In clinical studies, no clinically important differences in the pharmacokinetics of opicapone were observed when administered concomitantly with acetaminophen.1

MAO Inhibitors

Both opicapone and nonselective MAO inhibitors (e.g., phenelzine, isocarboxazid, tranylcypromine) inhibit catecholamine metabolism.1 Concomitant use of these drugs can therefore have additive effects on catecholamine levels, which may increase the risk of arrhythmias, increased heart rate, and excessive changes in blood pressure.1 Concomitant use of opicapone and nonselective MAO inhibitors is contraindicated.1 (See Contraindications under Cautions.)

In clinical studies, concomitant use of opicapone and selective MAO-B inhibitors (e.g., selegiline, rasagiline) did not result in any clinically important changes in the pharmacokinetics of the selective MAO-B inhibitor. 1 The manufacturer states that selective MAO-B inhibitors may be used concomitantly with opicapone. 1

Drugs Metabolized by COMT

Opicapone may alter the pharmacokinetics of drugs metabolized by COMT, which may increase the risk of adverse effects associated with these drugs (e.g., arrhythmias, increased heart rate, excessive changes in blood pressure).1 Drugs metabolized by COMT should be used cautiously with opicapone.1 Patients should be monitored for changes in heart rate, heart rhythm, and blood pressure.1

Protein-bound Drugs

In vitro studies indicate that opicapone does not alter the protein binding of other highly protein-bound drugs (e.g., warfarin, diazepam, digoxin, tolbutamide).1

Other Antiparkinsonian Drugs

Clinical studies have not revealed any clinically important pharmacokinetic interactions between opicapone and the following drugs used in the treatment of parkinson disease: rasagiline, selegiline, pramipexole, ropinirole, and amantadine.1

Description

Opicapone is a peripheral, selective, and reversible third-generation COMT inhibitor.1,2 Opicapone binds with high affinity to COMT, resulting in a slow complex dissociation rate conferring its long duration of action.2 The COMT enzyme catalyzes the metabolism of substrates containing a catechol structure including dihydroxyphenylalanine (DOPA), catecholamines (dopamine, norepinephrine, and epinephrine), and their metabolites.1,2 Decarboxylation is normally the major metabolic pathway for levodopa; however, when decarboxylation is prevented by carbidopa, COMT becomes the major metabolic pathway.1,2,13 Opicapone inhibits the metabolism of levodopa in peripheral tissues, thereby increasing its elimination half-life and delivery to the brain.2

The high binding affinity of opicapone results in sustained COMT inhibition and a long duration of action, allowing for once-daily administration.4 Administration of opicapone 50 mg daily inhibited COMT activity in erythrocytes with more than 65% of inhibitory activity maintained over the 24-hour dosing interval in patients with parkinson disease.1 Enzyme activity slowly returns to baseline after opicapone is discontinued.1 COMT inhibition of more than 35% is still seen 5 days following the last dose.1 Concomitant administration of opicapone with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased plasma levodopa concentrations compared with administration of levodopa and carbidopa alone.1 Opicapone increased peak plasma concentrations of levodopa by 43-44% and AUC by 62-94% compared with administration of levodopa/carbidopa alone.1

The pharmacokinetics of opicapone are dose proportional over the dose range of 25-50 mg.1 Peak plasma concentrations of the drug are reached approximately 2 hours after oral administration.1 Administration of opicapone with a moderate fat/moderate calorie meal decreases peak plasma concentrations by 62%, decreases AUC by 31%, and delays time to peak concentration by 4 hours.1 In one of the principal efficacy studies, opicapone was administered without regard to food, while in the other study, administration of opicapone was separated from food intake by 1 hour.1 (See Administration under Dosage and Administration.) Opicapone distributes peripherally and does not cross the blood-brain barrier.2 The drug is highly protein bound (more than 99%).1 Opicapone is primarily metabolized through sulfation; glucuronidation, methylation by COMT, reduction, and glutathione conjugation also are involved.1 The mean elimination half-life of opicapone is 1-2 hours.1 The primary route of excretion is fecal with 70% of a dose recovered in feces (22% as unchanged drug); 20% of the dose is expired in air, and 5% is excreted in urine (less than 1% as unchanged drug).1 Age, sex, and race/ethnicity do not have clinically important effects on the pharmacokinetics of opicapone.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.1
• Instruct patients and/or caregivers that opicapone capsules should be taken at bedtime.1 Inform patients to not eat food for 1 hour before and for at least 1 hour after intake of opicapone.1
• Advise patients and/or caregivers that somnolence has been reported with opicapone.1 Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living.1 These adverse reactions may affect the ability to drive and operate machinery safely.1
• Advise patients that opicapone may cause hypotension or syncope.1
• Advise patients that opicapone may cause dyskinesia or exacerbate pre-existing dyskinesia.1
• Advise patients that opicapone may cause hallucinations, delusions, or aggressive behavior, and to report any of these adverse reactions to their healthcare provider.1
• Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving opicapone and of advising them of the importance of reporting such urges.1
• Advise patients to contact their healthcare provider before stopping opicapone, and to inform their clinician if any symptoms such as fever, confusion, or severe muscle stiffness develop after the drug is discontinued.1
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Neurocrine Biosciences. Ongentys^® (opicapone) capsules prescribing information. San Diego, CA; 2020 Apr.

2. St Onge E, Vanderhoof M, Miller S. Ongentys (Opicapone): A New COMT Inhibitor for the Treatment of Parkinson's Disease. Ann Pharmacother . 2020; :1060028020974560. [PubMed 33233916]

3. Fox SH, Katzenschlager R, Lim SY et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease. Mov Disord . 2018; 33:1248-1266. [PubMed 29570866]

4. Ferreira JJ, Lees A, Rocha JF et al. Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol . 2016; 15:154-165. [PubMed 26725544]

5. Bausch Health. Tasmar® (tolcapone) tablets prescribing information. Bridgewater, NJ; 2020 Oct.

6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212489Orig1s000: Summary review. 2020 May 26. From FDA website.

7. Antonini A, Moro E, Godeiro C et al. Medical and surgical management of advanced Parkinson's disease. Mov Disord . 2018; 33:900-908. [PubMed 29570862]

8. Lees AJ, Ferreira J, Rascol O et al. Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol . 2017; 74:197-206. [PubMed 28027332]

9. Ferreira JJ, Lees A, Rocha JF et al. Long-term efficacy of opicapone in fluctuating Parkinson's disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions. Eur J Neurol . 2019; 26:953-960. [PubMedCentral][PubMed 30681754]

10. Reichmann H, Lees A, Rocha JF et al. Effectiveness and safety of opicapone in Parkinson's disease patients with motor fluctuations: the OPTIPARK open-label study. Transl Neurodegener . 2020; 9:9. [PubMedCentral][PubMed 32345378]

11. Ferreira JJ, Lees AJ, Poewe W et al. Effectiveness of opicapone and switching from entacapone in fluctuating Parkinson disease. Neurology . 2018; 90:e1849-e1857. [PubMed 29695590]

12. Lees A, Ferreira JJ, Rocha JF et al. Safety Profile of Opicapone in the Management of Parkinson's Disease. J Parkinsons Dis . 2019; 9:733-740. [PubMed 31498127]

13. Merck Sharp & Dohme. Sinemet® (carbidopa and levodopa) tablets prescribing information. Whitehouse Station, NJ; 2020 Mar.

101. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology . 2001; 56:S1-S88.

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116. PD Med Collaborative Group, Gray R, Ives N et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet . 2014; 384:1196-205. [PubMed 24928805]

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