Opicapone: A Pharmacological and Clinical Review for the Management of Parkinson's Disease

I. Introduction to Opicapone and its Therapeutic Context in Parkinson's Disease

A. Overview of Parkinson's Disease (PD) and "OFF" Episodes

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra, leading to a deficiency of dopamine in the brain.[1] This dopamine deficit manifests clinically as a constellation of motor symptoms, including bradykinesia (slowness of movement), rigidity, resting tremor, and postural instability. Levodopa, a dopamine precursor, remains the cornerstone of symptomatic therapy for PD.[2] However, long-term levodopa treatment is often complicated by the development of motor fluctuations, particularly "OFF" episodes.[3] These "OFF" episodes represent periods when the therapeutic effects of levodopa wear off, leading to the re-emergence or worsening of Parkinsonian motor symptoms such as shaking, stiffness, and slowed movement before the next scheduled dose.[4] Such fluctuations significantly impair patients' quality of life and functional independence, necessitating adjunctive therapeutic strategies to provide more continuous dopaminergic stimulation.[3]

B. Role of Catechol-O-Methyltransferase (COMT) Inhibition in Levodopa Therapy

Levodopa is administered in combination with a DOPA decarboxylase inhibitor (DDCI), such as carbidopa or benserazide, to prevent its premature peripheral conversion to dopamine, thereby increasing its central bioavailability and reducing peripheral side effects.[1] When DDC is inhibited, the enzyme catechol-O-methyltransferase (COMT) becomes the principal pathway for peripheral levodopa metabolism, converting it to 3-O-methyldopa (3-OMD).[2] 3-OMD is an inactive metabolite that competes with levodopa for active transport across the blood-brain barrier and does not possess anti-Parkinsonian activity, thus reducing the amount of levodopa reaching the brain and diminishing its therapeutic efficacy.[9]

COMT inhibitors are a class of pharmacological agents designed to block this peripheral degradation of levodopa. By inhibiting COMT, these drugs decrease the formation of 3-OMD, thereby increasing the plasma half-life and systemic bioavailability of levodopa. This leads to more sustained plasma levodopa concentrations and more consistent dopaminergic stimulation in the brain, which can alleviate "OFF" periods and improve motor control in patients with PD.[2]

C. Opicapone: A Third-Generation COMT Inhibitor

Opicapone, marketed under brand names including Ongentys and Ontilyv, is a potent, selective, reversible, and peripherally-acting third-generation COMT inhibitor.[3] It was developed to address some of the limitations associated with earlier COMT inhibitors. For instance, tolcapone, a first-generation COMT inhibitor, demonstrated efficacy but was associated with a risk of hepatotoxicity, requiring intensive liver function monitoring.[12] Entacapone, a second-generation inhibitor, has a better safety profile regarding liver function but possesses a relatively short duration of action, necessitating frequent administration with each levodopa dose.[12] Opicapone's development aimed to provide a COMT inhibitor with robust efficacy, a favorable safety profile, particularly concerning hepatotoxicity, and the convenience of once-daily dosing.[1]

Opicapone is indicated as an adjunctive therapy to preparations of levodopa/DDCI in adult patients with PD and end-of-dose motor fluctuations who cannot be stabilized on those combinations.[3] Its mechanism focuses on peripheral COMT inhibition, thereby enhancing the pharmacokinetic profile of levodopa without directly exerting central dopaminergic effects itself, although it potentiates the central effects of levodopa.[1] This peripheral selectivity is intended to maximize levodopa availability to the brain while potentially minimizing certain side effects associated with central COMT inhibition.

Key identifying information and approved uses for Opicapone are summarized in Table 1.

Table 1: Opicapone - Key Drug Information

Feature	Details	Source(s)
Generic Name	Opicapone	User Query, 7
Brand Names	Ongentys, Ontilyv	User Query, 3
DrugBank ID	DB11632	User Query, 7
CAS Number	923287-50-7	User Query, 11
Chemical Type	Small Molecule; Nitrobenzene, Oxadiazole, Pyridine N-oxide	User Query, 1
Developer	BIAL (Portela & Ca. S.A.)	3
Indication	Adjunct treatment to levodopa/carbidopa in adult patients with Parkinson's Disease experiencing "OFF" episodes or motor fluctuations.	User Query, 3

II. Pharmacological Profile of Opicapone

A. Chemical Properties and Formulation

Opicapone is classified as a small molecule drug [User Query]. Chemically, it is a nitrobenzene derivative belonging to the oxadiazole class and features a pyridine N-oxide moiety.[1] More specifically, it is described as a hydrophilic oxadiazole analog with a pyridine N-oxide at the 3rd position of its chemical structure.[1] Its molecular formula is C15​H10​Cl2​N4​O6​.[11]

Opicapone is commercially available as hard gelatin capsules in strengths of 25 mg and 50 mg.[1] The drug substance is considered flammable and requires storage at temperatures below 30°C, protected from moisture to maintain stability.[1]

B. Mechanism of Action: Selective and Peripheral COMT Inhibition

Opicapone exerts its therapeutic effect as a peripheral, selective, and reversible inhibitor of the COMT enzyme.[1] In patients treated with levodopa and a DDCI, COMT is the primary enzyme responsible for the peripheral O-methylation of levodopa into 3-O-methyldopa (3-OMD).[1] By inhibiting this enzymatic conversion in peripheral tissues, opicapone reduces the degradation of levodopa, thereby increasing its plasma concentrations and prolonging its plasma half-life. This enhanced systemic exposure allows a greater proportion of administered levodopa to cross the blood-brain barrier and be converted to dopamine in the central nervous system, thus augmenting its therapeutic effects in PD.[2]

A distinguishing characteristic of opicapone is its high binding affinity for the COMT enzyme, with reported affinities in the sub-picomolar range. This strong interaction leads to a slow dissociation rate of the opicapone-COMT complex, resulting in a prolonged duration of enzyme inhibition in vivo, significantly exceeding the drug's plasma half-life.[1] The presence of the pyridine N-oxide at the 3rd position of its structure is thought to contribute to both its potent inhibitory activity and its relatively minimized cellular toxicity.[1]

C. Pharmacokinetics (PK)

The pharmacokinetic profile of opicapone has been characterized in several studies.

• Absorption and Bioavailability: Opicapone is rapidly absorbed following oral administration, exhibiting a linear, dose-dependent absorption pattern.7 The oral bioavailability is estimated to be approximately 20%.7 After a single 50 mg oral dose, the median time to reach maximum plasma concentration (Tmax) is about 2 hours, with a range of 1 to 4 hours.7 A significant food effect on opicapone absorption has been documented. Administration with a moderate-fat or moderate-calorie meal can decrease the peak plasma concentration (Cmax) by approximately 62% and the mean overall plasma exposure (Area Under the Curve, AUC) by about 31%. Food also delays Tmax by approximately 4 hours.7 This interaction necessitates specific administration guidelines, advising patients to take opicapone at bedtime and to avoid food for at least one hour before and one hour after ingestion to ensure optimal and consistent absorption.1 Failure to adhere to these dietary instructions could lead to sub-optimal drug exposure and potentially reduced efficacy.
• Distribution: Opicapone is extensively bound to plasma proteins, with protein binding exceeding 99%. This binding is reported to be independent of drug concentration within the therapeutic range.7
• Metabolism: The primary metabolic pathway for opicapone is sulphation, which leads to the formation of an inactive metabolite, BIA 9-1103 (3-O-sulphated opicapone). This sulphated metabolite is the major circulating metabolite, accounting for approximately 67.1% of the total radioactivity observed in human studies with radiolabeled opicapone.7 Other metabolic transformations include glucuronidation, COMT-mediated methylation (forming BIA 9-1104, another circulating metabolite accounting for about 20.5% of total radioactivity), reduction, and conjugation with glutathione. Most other metabolites are generally found at unquantifiable levels in plasma samples.7 The predominance of sulphation as a metabolic route, rather than extensive CYP450-mediated metabolism, might suggest a lower potential for certain types of drug-drug interactions. However, as opicapone itself inhibits COMT, pharmacodynamic interactions with other COMT substrates remain a consideration.
• Excretion: Following oral administration of a single 100 mg dose of radiolabeled opicapone to healthy subjects, the majority of the dose (approximately 70%) was recovered in the feces, with about 22% of this fecal portion being unchanged opicapone. Approximately 20% of the dose was recovered in expired air (likely as CO2​ from metabolites), and about 5% was excreted in the urine. Less than 1% of the urinary excretion consisted of unchanged opicapone.4 The primary metabolite detected in urine is the glucuronide conjugate of opicapone.7 The mean elimination half-life of opicapone from plasma is relatively short, ranging from 1 to 2 hours.7 The apparent total body clearance after a 50 mg dose is approximately 22 L/h.7 Studies have indicated only minor systemic accumulation of opicapone after multiple once-daily doses.7

D. Pharmacodynamics (PD)

The pharmacodynamic effects of opicapone are primarily characterized by its potent and sustained inhibition of COMT activity and the consequent impact on levodopa pharmacokinetics.

• Extent and Duration of COMT Inhibition: Once-daily administration of opicapone 50 mg leads to a maximal inhibition of COMT activity in erythrocytes of approximately 84%.4 Importantly, this inhibition is sustained, remaining above 65% throughout the entire 24-hour dosing interval.4 The observed pharmacodynamic half-life of opicapone-induced COMT inhibition in human red blood cells is remarkably long, approximately 61.6 hours (standard deviation 37.6 hours), which is substantially longer than its plasma elimination half-life of 1-2 hours.7 This dissociation between plasma PK and enzyme inhibition duration is a key feature, often described as a "hit-and-run" mechanism, where the drug's effect persists long after its concentration in the plasma has declined. This is attributed to the high binding affinity and slow dissociation of opicapone from the COMT enzyme.1 Such sustained inhibition is the pharmacological basis for its effective once-daily dosing regimen, offering a significant advantage in convenience and potentially adherence over older COMT inhibitors requiring multiple daily doses.2 Even after discontinuation of treatment, COMT inhibition returns to baseline levels slowly, with greater than 35% inhibition still evident 5 days after the last dose.4
• Impact on Levodopa and 3-O-Methyldopa (3-OMD) Pharmacokinetics: The sustained COMT inhibition by opicapone translates directly into beneficial modifications of levodopa pharmacokinetics. Co-administration of opicapone with levodopa/DDCI significantly increases the systemic exposure to levodopa.8 Specifically, at steady-state, opicapone 50 mg has been shown to increase levodopa Cmax by an estimated 43-44% and total levodopa AUC by approximately 60% when levodopa/carbidopa (CD) is given every 3 hours (Q3H), and by 74% when levodopa/CD is given every 4 hours (Q4H).8 Furthermore, levodopa trough concentrations are approximately doubled.8 This enhancement of levodopa exposure is accompanied by a reduction in the peak-to-trough fluctuation index of levodopa concentrations by 32% to 46%.8 Concurrently, as expected from COMT inhibition, the plasma concentrations of 3-OMD (total AUC, Cmax, and trough concentrations) are significantly decreased.8 These pharmacokinetic changes—increased levodopa bioavailability, higher trough levels, and reduced fluctuations—are believed to underpin the clinical improvements in motor symptoms observed in PD patients.

Table 2: Summary of Opicapone Pharmacokinetic and Pharmacodynamic Parameters

Parameter	Value / Description	Source(s)
Oral Bioavailability	~20%	7
Median Tmax (50 mg single dose)	2 hours (range 1-4 hours)	7
Food Effect (Moderate fat/calorie meal)	Cmax ↓ by ~62%; AUC ↓ by ~31%; Tmax delayed by 4 hours	7
Plasma Protein Binding	>99%	7
Primary Metabolic Pathway	Sulphation (to inactive BIA 9-1103)	7
Major Metabolites	BIA 9-1103 (3-O-sulphated opicapone, ~67.1%); BIA 9-1104 (4-O-methylated opicapone, ~20.5%)	7
Excretion (100 mg radiolabeled dose)	Feces: ~70% (22% unchanged); Expired air: ~20%; Urine: ~5% (<1% unchanged)	4
Plasma Elimination Half-life	1-2 hours	7
Apparent Total Body Clearance (50 mg)	22 L/h	7
Maximal Erythrocyte COMT Inhibition (50mg)	~84%	4
Duration of COMT Inhibition (50mg)	>65% inhibition maintained over 24-hour interval; Pharmacodynamic t½ of inhibition ~61.6 hours; >35% inhibition 5 days post-last dose.	4
Effect on Levodopa PK (50mg OPC)	Cmax ↑ by 43-44%; Total AUC ↑ by 60-74%; Trough conc. approx. doubled; Peak-trough fluctuation index ↓ by 32-46%.	8

III. Clinical Efficacy in Parkinson's Disease

A. Overview of Pivotal Clinical Trials: BIPARK-I (NCT01568073) and BIPARK-II (NCT01227655)

The clinical efficacy of opicapone as an adjunctive treatment for Parkinson's disease was primarily established in two pivotal Phase III multinational, multicenter, randomized, double-blind, placebo-controlled trials: BIPARK-I (NCT01568073) and BIPARK-II (NCT01227655).[3] BIPARK-I also incorporated an active-comparator arm, evaluating opicapone against entacapone 200 mg, a then-standard COMT inhibitor.[3]

These trials enrolled adult patients aged 30–83 years with a diagnosis of idiopathic PD for at least three years, who were classified as Hoehn and Yahr stage 1–3 during their "ON" state. All participants were receiving a stable regimen of levodopa (for at least one year) in combination with a DDC inhibitor and were experiencing end-of-dose motor fluctuations, defined as a mean total awake "OFF" time of at least 1.5 hours daily, not including morning akinesia.[4]

In BIPARK-I, patients were randomized to receive opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg administered with each levodopa dose) for 14–15 weeks.[3] BIPARK-II randomized patients to opicapone (25 mg or 50 mg once daily) or placebo for a similar duration.[6] Following the double-blind phase, eligible patients could enter a 1-year open-label extension phase, during which they received active treatment with opicapone.[3] The primary efficacy endpoint in both studies was the change from baseline in absolute "OFF" time, as assessed by patient-completed diaries.[3]

B. Efficacy Results (focus on Opicapone 50 mg, the approved dose)

The 50 mg once-daily dose of opicapone emerged as the most effective and is the approved dosage.

• Reduction in Absolute "OFF" Time: In BIPARK-I (referred to as Study 1 in the FDA label), treatment with opicapone 50 mg resulted in a statistically significant mean reduction in absolute "OFF" time compared to placebo. The placebo-subtracted difference was -1.01 hours (approximately -60.6 minutes) (95% CI: -1.620, -0.407; p=0.002).4 Another report from this study indicated a least squares mean change from baseline in "OFF" time of -118.8 minutes for the 50 mg opicapone group versus -64.5 minutes for placebo, yielding an adjusted treatment difference of -54.3 minutes (95% CI, -96.2 to -12.4 minutes; P =.008).18 In BIPARK-II (Study 2 in the FDA label), opicapone 50 mg also demonstrated a statistically significant reduction in mean absolute "OFF" time versus placebo. The placebo-subtracted difference was -0.91 hours (approximately -54.6 minutes) (95% CI: -1.523, -0.287; p=0.008).4 These consistent findings across two large, well-controlled trials underscore opicapone's ability to meaningfully decrease the duration of "OFF" periods, which translates to approximately an extra hour of "ON" time for patients. This magnitude of improvement is considered clinically significant in the management of PD.
• Increase in "ON" Time without Troublesome Dyskinesia: In BIPARK-I, opicapone 50 mg led to a statistically significant increase in mean absolute "ON" time without troublesome dyskinesia when compared to placebo. The placebo-subtracted difference was 1.08 hours (95% CI: 0.440, 1.728; p=0.001).4 In BIPARK-II, while there was an increase in "ON" time without troublesome dyskinesia in the opicapone 50 mg group compared to placebo, this difference did not achieve statistical significance (placebo-subtracted difference: 0.62 hours; 95% CI: -0.039, 1.287; p=0.065).4
• UPDRS Scores: Detailed changes in the Unified Parkinson's Disease Rating Scale (UPDRS) scores are not consistently reported across the provided summaries of these trials.4
• Patient and Clinician Global Impression of Change (CGI-C, PGI-C): In BIPARK-I, a higher proportion of patients treated with opicapone 50 mg showed clinically meaningful improvements on both the Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C) scales compared to those treated with entacapone.14

C. Comparative Efficacy: Opicapone versus Entacapone (from BIPARK-I)

The BIPARK-I study provided a direct comparison between opicapone and entacapone. Opicapone 50 mg once daily was found to be non-inferior to entacapone 200 mg (taken with each levodopa dose) in reducing "OFF" time.[12] The mean change in "OFF" time was -116.8 minutes for opicapone 50 mg versus -96.3 minutes for entacapone.[12]

Notably, during the open-label extension phase of BIPARK-I, patients who were switched from entacapone to opicapone 50 mg experienced a further mean reduction in "OFF" time by an additional 39.3 minutes and a corresponding increase in "ON" time without troublesome dyskinesia by 45.7 minutes.[12] This observation suggests that opicapone may offer more sustained or potent COMT inhibition throughout the day due to its prolonged pharmacodynamic effect and once-daily dosing, potentially leading to better motor control compared to the more frequently dosed entacapone.

Furthermore, a post-hoc analysis of BIPARK-I indicated that opicapone treatment resulted in a greater proportion of patients "waking up ON" (i.e., with good motor control upon awakening) and a reduced time-to-"ON" after the first morning levodopa dose, compared to entacapone.[14] This benefit in managing morning akinesia could be particularly valuable for patients, as this is often a challenging period of the day. The sustained COMT inhibition by opicapone, facilitated by its bedtime dosing and long duration of action, likely contributes to better levodopa bioavailability from the first morning dose.

D. Long-Term Efficacy and Maintenance of Effect

The 1-year open-label extension phases of both BIPARK-I and BIPARK-II demonstrated that the beneficial effects of opicapone 50 mg on motor fluctuations were maintained over the long term.[3] In BIPARK-II's open-label phase, the reduction in "OFF" time was sustained, with a mean reduction of -126.3 minutes from the original baseline observed at the 1-year open-label endpoint for patients continuously treated with opicapone 50 mg.[18] Another analysis from the open-label phase reported an adjusted mean change from the start of the open-label phase in "OFF" time of -18.31 minutes, and a mean increase in total "ON" time of 24.9 minutes.[12] These data support the long-term utility of opicapone in managing motor fluctuations.

Table 3: Key Efficacy Outcomes from BIPARK-I and BIPARK-II (Opicapone 50 mg vs. Placebo and/or Entacapone)

Study	Treatment Arm	Endpoint	Baseline (Mean OFF-time, hrs approx.)	Change from Baseline (Mean)	Placebo-Subtracted Difference (95% CI)	p-value	Source(s)
BIPARK-I (Study 1)	Opicapone 50 mg	Absolute OFF-time (hours)	~5.0	-1.98 hours (-118.8 min)a	-1.01 hours (-60.6 min) (-1.620, -0.407)b	0.002$^\text{b}$	4
	Placebo	Absolute OFF-time (hours)	~4.9	-1.08 hours (-64.5 min)a	N/A	N/A	18
	Entacapone 200 mg	Absolute OFF-time (minutes)	N/A	-96.3 min$^\text{c}$	Opicapone 50mg non-inferior to Entacapone	0.0051$^\text{c}$	12
	Opicapone 50 mg	Absolute ON-time w/o troublesome dyskinesia (hours)	N/A	N/A	1.08 hours (0.440, 1.728)b	0.001$^\text{b}$	4
BIPARK-II (Study 2)	Opicapone 50 mg	Absolute OFF-time (hours)	~4.8	N/A	-0.91 hours (-54.6 min) (-1.523, -0.287)b	0.008$^\text{b}$	4
	Placebo	Absolute OFF-time (hours)	~4.7	N/A	N/A	N/A	4
	Opicapone 50 mg	Absolute ON-time w/o troublesome dyskinesia (hours)	N/A	N/A	0.62 hours (-0.039, 1.287)b	0.065$^\text{b}$	4
BIPARK-II (Open Label)	Opicapone 50 mg	Absolute OFF-time from original baseline (minutes) at 1 year	N/A	-126.3 min$^\text{a}$	N/A	N/A	18

Notes:

• N/A: Not explicitly available in the cited snippet for that specific format. Baseline OFF-times are approximate based on typical values in these patient populations.
• a As reported in [18] (Ferreira et al., 2016 for BIPARK-II).
• b As reported in [4] (FDA Label, Study 1 and Study 2).
• c As reported in [12] (comparative data from BIPARK-I).
• Differences in reported absolute values across sources may exist due to different statistical analysis sets or reporting conventions (e.g., least squares mean vs. simple mean). Placebo-subtracted differences are generally more consistent.

IV. Safety and Tolerability Profile

A. Overview of Adverse Events (AEs) from Clinical Trials

Opicapone was generally well-tolerated in the pivotal clinical trials.[3] The most common adverse reactions (defined as occurring in ≥4% of patients treated with Ongentys 50 mg and at a rate greater than placebo), based on pooled data from the BIPARK-I and BIPARK-II studies, are presented in Table 4.[4]

Table 4: Most Common Adverse Reactions Reported for Opicapone (≥4% and > placebo with 50 mg dose)

Adverse Reaction	Opicapone 50 mg (N=265) %	Placebo (N=257) %	Source(s)
Nervous system disorders
Dyskinesia	20	6	4
Dizziness	3	1	4
Gastrointestinal disorders
Constipation	6	2	4
Dry mouth	3	1	4
Psychiatric disorders
Hallucination	3	1	4
Insomnia	3	2	4
Investigations
Blood creatine kinase increased	5	2	4
Weight decreased	4	0	4
Vascular disorders
Hypotension/syncope	5	1	4
Hypertension	3	2	4

Dyskinesia was the most frequently reported adverse event and also the most common reason for treatment discontinuation in patients receiving opicapone.[4] This is an anticipated effect, as opicapone potentiates levodopa, and dyskinesia is a known dose-related side effect of levodopa. Careful adjustment of the levodopa dosage upon initiation of opicapone is often necessary to mitigate this effect.[9] Postmarketing surveillance has also identified falls as an adverse event.[17]

B. Specific Safety Considerations

• Hepatotoxicity: A significant advantage of opicapone is its favorable hepatotoxicity profile. Unlike the first-generation COMT inhibitor tolcapone, which carries a black-box warning for potentially fatal fulminant hepatic failure and requires regular liver enzyme monitoring 12, opicapone has not been associated with severe hepatic impairment or risk of hepatic failure in clinical trials.12 Its liver safety profile appears comparable to that of entacapone, which also has not demonstrated a significant risk of liver damage.10 The chemical structure of opicapone, particularly the pyridine N-oxide moiety, is thought to contribute to minimized cell toxicity.1 The European Public Assessment Report (EPAR) summary for Ongentys indicates that its safety was considered comparable to other medicines in its class, though specific comparative hepatotoxicity details with older inhibitors are not extensively detailed in the summary document itself.5
• Cardiovascular Effects: Opicapone can inhibit the metabolism of other drugs that are substrates for COMT, including catecholamines like isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine.4 Concomitant use may lead to increased plasma levels of these drugs, potentially causing arrhythmias, increased heart rate, and excessive changes in blood pressure. Therefore, monitoring of cardiovascular parameters is recommended when opicapone is co-administered with such agents.4 Hypertension was reported in 3% of opicapone-treated patients versus 2% in the placebo group in clinical trials.4
• Dopaminergic Side Effects: As opicapone enhances the effects of levodopa, an increase in dopaminergic side effects can occur.
• Dyskinesia: As noted, this is the most common side effect.[4] Dose reduction of levodopa or other dopaminergic medications may be required.[9]
• Hallucinations and Psychosis: These can occur or be exacerbated. If they develop, discontinuation of opicapone should be considered. Patients with a pre-existing major psychotic disorder should generally not be treated with opicapone.[4]
• Impulse Control/Compulsive Disorders: Patients may experience intense urges (e.g., pathological gambling, increased libido, compulsive spending, binge eating) and an inability to control these urges. Prescribers should inquire about the development of new or increased urges during treatment.[4]
• Somnolence and Falling Asleep During Daily Activities: Patients treated with opicapone and other dopaminergic therapies have reported falling asleep while engaged in activities of daily living, sometimes without prior warning signs of drowsiness. This can include driving, potentially leading to accidents. Caution should be exercised, and patients should be advised to avoid driving and other potentially dangerous activities if they experience significant somnolence. Discontinuation of opicapone or adjustment of other sedating medications may be necessary.4
• Hypotension/Syncope: Opicapone may cause or worsen hypotension, potentially leading to syncope. Blood pressure should be monitored, especially during dose initiation and titration. If symptomatic hypotension occurs, discontinuation of opicapone or adjustment of concomitant antihypertensive medications should be considered.4 The incidence was 5% with opicapone versus 1% with placebo.4
• Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (NMS), characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability, has been reported with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Patients should be monitored carefully if opicapone is discontinued or the dose is rapidly reduced.4
• Rhabdomyolysis Risk: An increase in blood creatine kinase (CK) levels was observed in 5% of opicapone-treated patients compared to 2% in the placebo group.4 While rhabdomyolysis itself has not been directly linked to opicapone in the provided information 21, elevated CK can be an indicator of muscle injury. Therefore, patients should be monitored for unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.
• Urine Discoloration: Unlike entacapone, which commonly causes a harmless reddish-orange discoloration of urine 10, opicapone is uncommonly associated with this effect. Only two cases of chromaturia (urine discoloration) were considered related to the 25 mg dose of opicapone in the pivotal trials.14
• Diarrhea: Opicapone has a favorable gastrointestinal tolerability profile concerning diarrhea. In contrast to entacapone, which is associated with a notable incidence of diarrhea, sometimes severe and delayed in onset 10, treatment-related diarrhea has not been a significant observation with opicapone.14

C. Contraindications

Opicapone is contraindicated in patients with:

• Concomitant use of non-selective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid) due to the risk of hypertensive crisis from increased catecholamine levels.[1]
• Pheochromocytoma, paraganglioma, or other catecholamine-secreting neoplasms, as COMT inhibition could lead to excessive catecholamine release from these tumors.[1]
• A history of hypersensitivity to opicapone or any of its excipients.

D. Warnings and Precautions

The warnings and precautions associated with opicapone use are largely related to the potentiation of levodopa's effects and the general risks associated with dopaminergic therapies. These include cardiovascular effects with concomitant use of drugs metabolized by COMT, falling asleep during activities of daily living and somnolence, hypotension/syncope, dyskinesia, hallucinations and psychosis, impulse control disorders, and the potential for withdrawal-emergent hyperpyrexia and confusion.[4]

E. Drug Interactions

• Non-selective MAO Inhibitors: Co-administration is contraindicated. The combination can inhibit catecholamine metabolism significantly, leading to increased systemic levels of catecholamines and potentially life-threatening cardiovascular events such as hypertensive crisis.[4] However, selective MAO-B inhibitors (e.g., selegiline, rasagiline), which are commonly used in PD, can be used concomitantly with opicapone.[17]
• Drugs Metabolized by COMT: Caution is advised when opicapone is co-administered with other drugs that are substrates for COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, and apomorphine.[4] Opicapone may inhibit their metabolism, leading to increased plasma concentrations and an augmented risk of cardiovascular side effects (e.g., arrhythmias, increased heart rate, excessive blood pressure changes). Patients receiving such combinations should be monitored closely.[4]
• Other Potential Interactions: The UK Patient Information Leaflet for Ongentys mentions potential interactions where opicapone may increase the effects of methotrexate, certain statins (rosuvastatin, simvastatin, atorvastatin, pravastatin), and quinidine.[16] However, the FDA label notes that opicapone is a substrate of various transporters (P-gp, BCRP, MRP2, OATP1B2, OATP2B1) but no clinically significant transporter-mediated interactions are expected for opicapone itself via these transporters.[17] The clinical significance of these interactions should be considered, and official prescribing information from relevant regulatory authorities should be consulted.

V. Dosage, Administration, and Regulatory Status

A. Recommended Dosing Regimen and Administration Instructions

The recommended dosage of opicapone (Ongentys) is 50 mg administered orally once daily at bedtime.[1] It is crucial that patients take opicapone on an empty stomach, specifically at least 1 hour before or at least 1 hour after food consumption, to ensure optimal absorption and consistent efficacy due to the significant food effect on its pharmacokinetics.[1] The capsule should be swallowed whole with a glass of water.[16] Bedtime administration is preferred and may help manage potential immediate post-dose side effects, such as somnolence or dyskinesia, by having their peak onset occur during the patient's sleep period.

B. Dosage Adjustments in Special Populations

• Hepatic Impairment:
• For patients with mild hepatic impairment (Child-Pugh Class A), no dosage adjustment of opicapone is necessary.[1]
• In patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dosage is reduced to 25 mg orally once daily at bedtime.[1]
• Opicapone should be avoided in patients with severe hepatic impairment (Child-Pugh Class C) due to a lack of clinical data in this population and the potential for increased drug exposure.[1] This suggests that liver function significantly impacts opicapone exposure, even though its primary metabolism is via sulphation, indicating that overall metabolic capacity can be compromised in severe liver disease.
• Renal Impairment:
• For patients with mild to moderate renal impairment (Creatinine Clearance [CrCl] 30-89 mL/min), no dosage adjustment is required.[17]
• Opicapone has not been studied in patients with severe renal impairment (CrCl <30 mL/min). Due to the potential for increased exposure, these patients should be monitored closely for adverse reactions, and therapy should be discontinued if tolerability issues arise.[17]
• Use of opicapone should be avoided in patients with end-stage renal disease (ESRD) (CrCl <15 mL/min).[17]
• Geriatric Population: The dosing recommendations for geriatric patients are similar to those for the general adult population.1
• Pediatric Use: Opicapone is not indicated for use in children and adolescents, and there is no clinical experience in this population.16

C. Discontinuation and Missed Dose

If opicapone treatment is discontinued, patients should be monitored, and adjustment of other dopaminergic therapies may be necessary to manage Parkinson's symptoms.[4] If a dose is missed, the patient should not take a double dose to compensate for the forgotten dose; they should take the next dose at the usual scheduled time.[16]

D. Global Regulatory Approvals and Marketing Information

Opicapone was developed by BIAL (Portela & Ca. S.A.).[1]

• European Medicines Agency (EMA) Approval: Opicapone, under the brand name Ongentys, received marketing authorization from the European Commission in June 2016.[1] It is indicated in the European Union as adjunctive therapy to preparations of levodopa/DDCIs in adult patients with Parkinson's disease and end-of-dose motor fluctuations who cannot be stabilized on those combinations.[3] As of 2020, it was marketed in Germany, the United Kingdom, Spain, Portugal, and Italy.[3]
• U.S. Food and Drug Administration (FDA) Approval: The FDA approved Ongentys (opicapone) in April 2020.[1] The U.S. indication is as an adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing “off” episodes.[4]
• U.S. Marketer History: Initially, BIAL granted an exclusive licensing agreement to Neurocrine Biosciences for the development and commercialization of opicapone in the U.S. and Canada, with a commercial launch by Neurocrine in September 2020.[3] However, Neurocrine Biosciences provided BIAL with written notice of termination of this license agreement in May 2023.[15] As of April 2025, the FDA approval information for Ongentys lists Amneal Pharmaceuticals as the manufacturer/marketer in the United States.[20] Such changes in marketing partnerships are commercial dynamics that typically do not alter the drug's approved uses or intrinsic properties but may affect market availability and support programs.

E. Brand Names and Formulations

Opicapone is marketed under the brand names Ongentys 3 and Ontilyv.7

It is available in 25 mg and 50 mg hard gelatin capsules.1

• The 50 mg capsules have a dark blue opaque cap and a dark pink opaque body, axially printed with “OPC” over “50” in white ink on both the cap and body.[4]
• The 25 mg capsules have a light blue opaque cap and a light pink opaque body, axially printed with “OPC” over “25” in blue ink on both the cap and body.[4]

Table 5: Opicapone Dosage Recommendations in Special Populations

Population	Recommended Dosage / Action	Source(s)
Hepatic Impairment
Mild (Child-Pugh A)	No dosage adjustment necessary	1
Moderate (Child-Pugh B)	25 mg orally once daily at bedtime	1
Severe (Child-Pugh C)	Avoid use	1
Renal Impairment
Mild to Moderate (CrCl 30-89 mL/min)	No dosage adjustment necessary	17
Severe (CrCl <30 mL/min)	Not studied; monitor for adverse reactions, discontinue if tolerability issues arise due to potential increased exposure.	17
End-Stage Renal Disease (ESRD) (CrCl <15 mL/min)	Avoid use	17

VI. Conclusion and Clinical Implications

A. Summary of Opicapone's Profile

Opicapone is a third-generation, peripherally-acting, selective, and reversible COMT inhibitor administered once daily. Clinical evidence from the pivotal BIPARK-I and BIPARK-II trials has robustly demonstrated its efficacy as an adjunctive therapy to levodopa/DDCI in adult patients with Parkinson's disease experiencing "OFF" episodes.[3] The 50 mg once-daily dose significantly reduces "OFF" time and correspondingly increases "ON" time, with these benefits maintained over long-term treatment. A key characteristic of opicapone is its unique pharmacokinetic/pharmacodynamic profile, where a short plasma half-life is coupled with a very long duration of COMT inhibition, supporting the convenient once-daily dosing regimen.[7] Furthermore, opicapone exhibits a favorable safety profile, particularly with regard to hepatotoxicity, which was a significant concern with the earlier COMT inhibitor, tolcapone.[12] It also appears to have better gastrointestinal tolerability concerning diarrhea compared to entacapone.[14]

B. Positioning in the Management of Parkinson's Disease

Opicapone represents a valuable addition to the therapeutic armamentarium for managing motor fluctuations in Parkinson's disease.[3] Its combination of efficacy, once-daily administration, and an improved safety profile positions it as an attractive COMT inhibitor choice for many patients. The convenience of once-daily dosing may enhance patient adherence compared to older COMT inhibitors that require multiple daily administrations synchronized with levodopa doses.[12] The favorable liver safety profile alleviates the need for intensive hepatic monitoring associated with tolcapone. Post-hoc analyses also suggest potential benefits in specific scenarios, such as improving morning akinesia, which can be particularly disabling for patients.[14] Some evidence suggests enhanced efficacy in patients who are in earlier stages of their disease course and levodopa treatment pathway, hinting at a potential role for earlier adjunctive use to optimize levodopa therapy and possibly delay the progression of motor complications.[6]

C. Unmet Needs and Future Perspectives

While opicapone addresses several limitations of previous COMT inhibitors, some considerations remain. The prescribing information notes that long-term cardiovascular safety has not been definitively established, which is a general point for many chronic medications.[4] Further real-world evidence and long-term observational studies will continue to refine its place in therapy and confirm its long-term safety and effectiveness across diverse patient populations. The impact on non-motor symptoms and detailed UPDRS subscale changes could be areas for further exploration if not fully elucidated in existing publications.

Overall, opicapone stands out as a significant refinement in COMT inhibitor therapy. Its unique pharmacological properties translate into tangible clinical benefits for patients with Parkinson's disease struggling with motor fluctuations. The successful introduction of opicapone encourages a re-evaluation of treatment strategies for "wearing-off," potentially supporting earlier and broader use of COMT inhibition. Effective utilization in clinical practice hinges on appropriate patient selection, thorough counseling regarding administration (particularly the food interaction and bedtime dosing), and proactive management of dopaminergic side effects, primarily through careful titration and adjustment of concomitant levodopa therapy.

Works cited

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2. What is the mechanism of Opicapone? - Patsnap Synapse, accessed May 12, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-opicapone
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