Ongentys (Opicapone)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson’s disease — adjunctive to levodopa/carbidopa in patients experiencing “off” episodes | Adults | Always adjunctive to LD/DDCI | FDA Approved (2020) |
Opicapone is a third-generation, peripherally selective, reversible COMT inhibitor that represents an advance over entacapone in two key respects: once-daily dosing (rather than with every levodopa dose) and more potent, sustained COMT inhibition (>24 hours). In preclinical models, opicapone achieved 99% COMT inhibition at 1 hour versus 68% for entacapone; at 9 hours, opicapone maintained 91% inhibition whereas entacapone had no detectable effect. This sustained pharmacodynamic profile reflects opicapone’s tight binding to the COMT enzyme with very slow dissociation, resulting in a COMT inhibition half-life of 60–130 hours — far exceeding the parent drug’s plasma half-life of 1–2 hours — and enabling once-daily bedtime administration.
Once-daily dosing (vs with each LD dose), more potent and sustained COMT inhibition, no clinically significant diarrhea or colitis risk, and no hepatotoxicity concerns. Like entacapone, no mandatory liver function monitoring is required.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PD with off episodes — standard | 50 mg once daily at bedtime | 50 mg once daily | 50 mg/day | No titration required; take on empty stomach No food 1 h before and ≥1 h after dosing (food reduces AUC by 31%) |
| Moderate hepatic impairment (Child-Pugh B) | 25 mg once daily at bedtime | 25 mg once daily | 25 mg/day | AUC increased ~84% in moderate hepatic impairment (FDA PI) |
| Mild hepatic impairment (Child-Pugh A) | 50 mg once daily | Standard | 50 mg/day | AUC increased ~35%; not clinically significant; no adjustment |
| Severe hepatic impairment (Child-Pugh C) | Avoid use; not studied | |||
| Renal impairment (CrCl 15–89) | 50 mg once daily | Standard | 50 mg/day | Monitor for adverse effects in severe renal impairment; renal route plays minor role |
| End-stage renal disease (CrCl <15) | Avoid use (FDA PI) | |||
| Switching from entacapone | 25 mg once daily at bedtime | Increase to 50 mg after 1 week if needed | 50 mg/day | Stop entacapone on the same day; start opicapone at bedtime Based on BIPARK-I switching protocol |
| Elderly (≥65 years) | 50 mg once daily | Standard | 50 mg/day | 52% of trial patients were ≥65; no dose adjustment needed |
Food significantly reduces opicapone absorption (Cmax −62%, AUC −31%, Tmax delayed 4 hours). Bedtime dosing on an empty stomach is recommended, as it separates the dose from meals and provides COMT inhibition throughout the following day’s levodopa doses. Unlike entacapone, there is no need to adjust the dosing frequency — one capsule at bedtime covers all next-day levodopa doses.
Rapid withdrawal of drugs that increase central dopaminergic tone, including opicapone via its effect on levodopa, can trigger a symptom complex resembling neuroleptic malignant syndrome. When discontinuing, monitor patients and adjust other dopaminergic therapies as needed.
Pharmacology
Mechanism of Action
Opicapone is a selective, reversible, peripherally acting COMT inhibitor that blocks the O-methylation of levodopa to 3-O-methyldopa in peripheral tissues. Its high binding affinity and very slow dissociation from the COMT enzyme result in sustained inhibition that persists well beyond the elimination of the parent compound from plasma. Despite a short plasma half-life of 1–2 hours, the half-life of erythrocyte COMT inhibition is 60–130 hours, reflecting opicapone’s tight enzyme binding rather than circulating drug or metabolite activity. The major circulating metabolite is the pharmacologically inactive 3-O-sulfate (BIA 9-1103, t½ 94–122 hours); a minor reduced metabolite (BIA 9-1079, <10%) has some COMT inhibitory activity in preclinical studies. This unique pharmacodynamic profile enables once-daily bedtime dosing with sustained COMT inhibition across all next-day levodopa doses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~2 h (range 1–2.5 h); bioavailability ~20%; moderate-fat meal reduces Cmax by 62% and AUC by 31%, delays Tmax by 4 h | Must take on empty stomach (1 h before and ≥1 h after food); bedtime dosing facilitates this requirement |
| Distribution | Protein binding >99%; does not cross BBB; peripherally selective; does not affect protein binding of warfarin, digoxin, diazepam, or tolbutamide in vitro | Very high protein binding limits tissue distribution; no displacement interactions expected at therapeutic concentrations |
| Metabolism | Primarily to 3-O-sulfate (BIA 9-1103, 67% of circulating drug, inactive), methylated derivative (21%, inactive), reduced derivative (BIA 9-1079, <10%, active in preclinical studies), and glucuronide (inactive); non-CYP mediated; no CYP inhibition or induction | Sulfate metabolite (BIA 9-1103) has t½ 94–122 h but is pharmacologically inactive; sustained >24 h COMT inhibition is due to opicapone’s tight enzyme binding, not circulating metabolite activity; no CYP-based drug interactions |
| Elimination | Parent t½ 1–2 h; ~70% recovered in faeces (22% as unchanged drug); renal elimination plays a minor role in clearance | Rapid parent elimination but sustained pharmacodynamic effect via long-lived metabolite; hepatic impairment increases exposure (biliary excretion is major route) |
Side Effects
Data from pooled BIPARK-I and BIPARK-II pivotal trials (N=750 total; 265 on opicapone 50 mg, 244 on 25 mg, 257 on placebo). Most adverse effects are dopaminergic, resulting from enhanced levodopa exposure. Notably, significant diarrhea and colitis — the key tolerability issues with entacapone — are not characteristic of opicapone.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dyskinesia | 18.3% (vs 6.2% placebo; pooled analysis) | Most common adverse effect; usually occurs within first 2–3 weeks; after LD dose adjustment, rate decreases to ~8.3% (vs 1.6% placebo); severe in only 1.2% |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Constipation | 5.7% (vs 1.9% placebo) | Unlike entacapone (where diarrhea predominates), constipation is the GI concern with opicapone |
| Blood creatine kinase increased | ≥4% > placebo | Monitor CPK if muscle symptoms arise; usually asymptomatic elevations |
| Hypotension / syncope | ≥4% > placebo | Dopaminergic mechanism; caution during dose adjustment period; lying/standing BP |
| Weight decreased | ≥4% > placebo | Monitor body weight; may relate to enhanced dopaminergic tone or reduced appetite |
| Insomnia | 5.1% (vs 1.6% placebo) | Pooled analysis data; bedtime dosing does not appear to worsen |
| Dry mouth | 4.7% (vs 1.2% placebo) | May overlap with anticholinergic medications in PD regimen |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hallucinations / psychosis | Uncommon (<5%) | Variable; increased dopaminergic tone | Consider stopping opicapone; patients with major psychotic disorders should not ordinarily receive opicapone |
| Impulse control disorders | Uncommon (class effect) | Weeks to months | Screen at every visit; consider dose reduction of dopaminergic therapy; involve caregivers |
| Withdrawal-emergent hyperpyrexia / NMS-like syndrome | Rare (class effect) | During rapid withdrawal of dopaminergic therapy | Taper gradually; monitor temperature, CPK, mental status |
| Syncope | ≥4% > placebo | Usually during dose adjustment period | Monitor BP; adjust concurrent antihypertensives; ensure adequate hydration |
Dyskinesia (18.3%) is the most common adverse effect and typically occurs within the first 2–3 weeks of treatment. In the pivotal trials, after an initial levodopa/carbidopa dose adjustment period, dyskinesia rates decreased substantially (8.3% opicapone vs 1.6% placebo). Most patients can start opicapone without changing their LD/CD regimen, adjusting only if dyskinesia emerges. Severe dyskinesia was uncommon (1.2% vs 0.8% placebo).
Drug Interactions
Opicapone has a cleaner interaction profile than CYP-metabolised drugs. It does not inhibit or induce major CYP enzymes and has no clinically significant PK interactions with warfarin, repaglinide, rasagiline, selegiline, pramipexole, ropinirole, or amantadine (all studied per FDA PI).
Monitoring
- DyskinesiaClosely for first 2–3 weeks
RoutineMost common adverse effect (18.3%); usually resolves with LD dose adjustment. After initial adjustment period, rate drops to ~8.3%. - Blood PressureBaseline, each visit
RoutineHypotension/syncope among most common adverse reactions (≥4% > placebo). Lying and standing measurements. - NeuropsychiatricEach visit
RoutineScreen for hallucinations, psychosis, ICDs (gambling, hypersexuality, spending). Patients with major psychotic disorders should not ordinarily receive opicapone. - Body WeightEach visit
RoutineWeight decrease among most common adverse reactions per FDA PI. - Creatine KinaseIf muscle symptoms arise
Trigger-BasedBlood CPK increase reported (≥4% > placebo); usually asymptomatic. Check if myalgia, weakness, or dark urine occur. - Hepatic FunctionBaseline (if risk factors)
Trigger-BasedNo mandatory LFT monitoring required (unlike tolcapone). Check baseline if hepatic disease suspected — moderate impairment requires 25 mg dose; severe is contraindicated. - Skin ExaminationAnnually
RoutinePD patients have elevated melanoma risk (disease-related). No melanoma cases in opicapone trials.
Contraindications & Cautions
Absolute Contraindications
- Concomitant non-selective MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) — risk of hypertensive crisis.
- Pheochromocytoma, paraganglioma, or other catecholamine-secreting neoplasms — COMT inhibition blocks catecholamine degradation.
Relative Contraindications (Specialist Input Recommended)
- Major psychotic disorder: Opicapone may exacerbate psychosis via enhanced dopaminergic tone.
- Severe hepatic impairment (Child-Pugh C): Not studied; avoid use.
- End-stage renal disease (CrCl <15 mL/min): Avoid use (FDA PI).
Use with Caution
- Moderate hepatic impairment (Child-Pugh B): AUC increased ~84%; reduce to 25 mg once daily.
- Severe renal impairment (CrCl 15–29): Monitor for adverse effects; discontinue if tolerability issues arise.
- History of NMS or non-traumatic rhabdomyolysis: EMA contraindicates; FDA PI advises caution.
Patients treated with dopaminergic medications, including opicapone in combination with levodopa, have reported suddenly falling asleep without warning during daily activities including driving. Patients should be advised not to drive or engage in hazardous activities until they have gained sufficient experience with the medication.
Patient Counselling
Purpose of Therapy
Opicapone helps your levodopa medication work more effectively throughout the day by blocking an enzyme that breaks down levodopa in your body. Unlike some similar medications, you only need to take opicapone once a day at bedtime, and it works continuously to extend the benefit of every levodopa dose you take the next day.
How to Take
Take one capsule at bedtime on an empty stomach. Do not eat for at least 1 hour before and 1 hour after taking the capsule. Food significantly reduces how well the medication is absorbed.
Sources
- ONGENTYS (opicapone) Capsules — FDA Prescribing Information. Initial approval 2020; revised 2025. accessdata.fda.govPrimary regulatory source for dosing (50 mg QD at bedtime), hepatic/renal adjustments, adverse reaction data, PK parameters, and contraindications.
- ONGENTYS (opicapone) Capsules — FDA Prescribing Information. 2020 original label. accessdata.fda.govOriginal FDA approval label; source for clinical study design (BIPARK-I/II) and PK drug interaction data.
- ONGENTYS (opicapone) — DailyMed Label. dailymed.nlm.nih.govCurrent DailyMed listing confirming dosing, contraindications, and adverse reaction profile.
- 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(2):154–165. doi:10.1016/S1474-4422(15)00336-1BIPARK-I pivotal trial: opicapone 50 mg significantly reduced off-time vs placebo; active-controlled arm included entacapone.
- 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(2):197–206. doi:10.1001/jamaneurol.2016.4703BIPARK-II pivotal trial: confirmed efficacy of opicapone 50 mg in reducing off-time; supported FDA approval.
- Lees A, Ferreira JJ, Rocha JF, et al. Safety profile of opicapone in the management of Parkinson’s disease. J Parkinsons Dis. 2019;9(4):733–740. doi:10.3233/JPD-191593Pooled safety analysis of BIPARK-I/II (N=750); source for dyskinesia 18.3% vs 6.2%, constipation 5.7%, insomnia 5.1% figures.
- 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(8):1248–1266. doi:10.1002/mds.27372MDS evidence review classifying opicapone as “efficacious” for reducing off-time in motor fluctuations (updated classification).
- Kiss LE, Soares-da-Silva P. Medicinal chemistry of catechol-O-methyltransferase (COMT) inhibitors and their therapeutic utility. J Med Chem. 2014;57(21):8692–8717. doi:10.1021/jm500572bComprehensive review of COMT inhibitor chemistry; describes opicapone’s tight-binding, slow off-rate mechanism and comparison with tolcapone/entacapone.
- Bonifacio MJ, Palma PN, Almeida L, Soares-da-Silva P. Catechol-O-methyltransferase and its inhibitors in Parkinson’s disease. CNS Drug Rev. 2007;13(3):352–379. doi:10.1111/j.1527-3458.2007.00020.xOverview of COMT biology and pharmacology; provides context for the development of third-generation COMT inhibitors.
- Opicapone. In: Drugs.com Monograph for Professionals. drugs.com/monographConsolidated professional monograph with PK data, drug interaction summary, and dosing guidance including entacapone switching protocol.
- Ferreira JJ, Lees A, Santos A, Hernandez B, Rocha JF, Soares-da-Silva P. Effect of opicapone on levodopa pharmacokinetics in patients with fluctuating Parkinson’s disease. Mov Disord. 2022;37(12):2448–2456. doi:10.1002/mds.29193Phase II PK study demonstrating opicapone 50 mg increases LD bioavailability with avoidance of trough levels even at lower LD doses.
- Rocha JF, Almeida L, Falcão A, et al. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013;76(5):763–775. doi:10.1111/bcp.12081Key Phase I PK study defining the short parent t½ (1–2 h), long sulfate metabolite t½ (94–122 h), and >24 h COMT inhibition duration.
- Reichmann H, Gurévich T, Gama H, Soares-da-Silva P. Evaluating opicapone as add-on treatment to levodopa/DDCI in patients with Parkinson’s disease. Degener Neurol Neuromuscul Dis. 2022;12:61–74. PMC9365060Comprehensive review of BIPARK pooled data, COMT inhibition comparisons (opicapone 99% vs entacapone 68%), and long-term safety data.