Ongentys is indicated as adjunctive therapy to preparations of levodopa/ DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease and end- of-dose motor fluctuations who cannot be stabilised on those combinations.

Posology The recommended dose is 50 mg of opicapone. Ongentys should be taken once-daily at bedtime at least one hour before or after levodopa combinations. Dose adjustments of antiparkinsonian therapy Ongentys is to be administered as an adjunct to levodopa treatment and enhances the effects of levodopa. Hence, it is often necessary to adjust levodopa dose by extending the dosing intervals and/or reducing the amount of levodopa per dose within the first days to first weeks after initiating the treatment with opicapone according to the clinical condition of the patient (see section 4.4). Missed dose If one dose is missed, the next dose should be taken as scheduled. The patient should not take an extra dose to make up for the missed dose. Special populations Elderly No dose adjustment is needed for elderly patients (see section 5.2). Caution must be exercised in patients = 85 years of age as there is limited experience in this age group. Renal impairment No dose adjustment is necessary in patients with renal impairment, as opicapone is not excreted by the kidney (see section 5.2). Hepatic impairment No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh Class B). Caution must be exercised in these patients and dose adjustment may be necessary (see section 5.2). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh Class C), therefore, opicapone is not recommended in these patients (see section 5.2). Paediatric population There is no relevant use of Ongentys in the paediatric population with Parkinson’s disease and motor fluctuations. Method of administration Oral use. The capsules should be swallowed whole with water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Phaeochromocytoma, paraganglioma, or other catecholamine secreting neoplasms. History of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis. Concomitant use with monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine and moclobemide) other than those for the treatment of Parkinson’s disease (see section 4.5).

Dose adjustments of antiparkinsonian therapy Ongentys is to be administered as an adjunct to levodopa treatment. Hence, the precautions valid for levodopa treatment should also be taken into account for Ongentys. Opicapone enhances the effects of levodopa. To reduce levodopa-related dopaminergic adverse reactions (e.g. dyskinesia, hallucinations, nausea, vomiting and orthostatic hypotension), it is often necessary to adjust the daily dose of levodopa by extending the dosing intervals and/or reducing the amount of levodopa per dose within the first days to first weeks after initiating treatment with Ongentys, according to the clinical condition of the patient (see section 4.2). If Ongentys is discontinued it is necessary to adjust the dosing of the other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the symptoms. Psychiatric disorders Patients and care-givers should be made aware that impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. Patients should be monitored regularly for the development of impulse control disorders and review of treatment is recommended if such symptoms develop. Others Increases in liver enzymes were reported in studies with nitrocatechol inhibitors of catechol- Omethyltransferase (COMT). For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered. Excipients Ongentys contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Ongentys contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Monoamino oxidase (MAO) inhibitors Combination of opicapone and MAO inhibitors could result in inhibition of the majority of the pathways responsible for the metabolism of catecholamines. Because of this, concomitant use of opicapone with MAO inhibitors (e.g. phenelzine, tranylcypromine and moclobemide) other than those for the treatment of Parkinson’s disease is contraindicated (see section 4.3). Concomitant use of opicapone and MAO inhibitors for the treatment of Parkinson’s disease, e.g. rasagiline (up to 1 mg/day) and selegiline (up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption formulation), is permissible. There is no experience with opicapone when used concomitantly with the MAO-B inhibitor safinamide. Therefore, their concomitant use should be considered with appropriate caution. Medicinal products metabolised by COMT Opicapone may interfere with the metabolism of medicinal products containing a catechol group that are metabolised by COMT, e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dopexamine or dobutamine, leading to potentiated effects of these medicinal products. Careful monitoring of patients being treated with these medicinal products is advised when opicapone is used. Tricyclic antidepressants and noradrenaline re-uptake inhibitors There is limited experience with opicapone when used concomitantly with tricyclic antidepressants and noradrenaline re-uptake inhibitors (e.g. venlafaxine, maprotiline and desipramine). Thus, their concomitant use should be considered with appropriate caution. Quinidine A study conducted in healthy volunteers showed that when a single dose of 50 mg opicapone was coadministered (within 1 hour) with a single dose of quinidine (600 mg), systemic exposure of opicapone decreased by 37% (AUC0-tlast). Thus, particular consideration should be given to cases where quinidine needs to be administered together with opicapone as their co-administration should be avoided. CYP2C8 and OATP1B1 substrates Opicapone is a weak in vitro inhibitor of CYP2C8 and OATP1B1, whereas repaglinide is a sensitive CYP2C8 and OATP1B1 substrate. A study conducted in healthy subjects showed that there were no changes in repaglinide’s exposure when repaglinide was administered following multiple once-daily administration of opicapone 50 mg.

Pregnancy There are no or limited amount of data from the use of opicapone in pregnant women. Opicapone crossed the placenta in rats. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Ongentys is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding Opicapone levels in the milk of lactating rats were equivalent to those in plasma. It is unknown whether opicapone or its metabolites are excreted into human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Ongentys. Fertility The effects of opicapone on fertility in humans have not been studied. Animal studies with opicapone do not indicate harmful effects with respect to fertility (see section 5.3).

Opicapone in association with levodopa may have major influence on the ability to drive and use machines. Opicapone may, together with levodopa, cause dizziness, symptomatic orthostatism and somnolence. Therefore, caution should be exercised when driving or using machines.

Summary of the safety profile The most common adverse reactions reported were nervous system disorders. Dyskinesia was the most frequently reported treatment-emergent adverse reaction (17.7%). Tabulated list of adverse reactions In the table below (Table 1) all adverse reactions are presented by System Organ Class and frequency. Frequency categories are defined as follows: very common (= 1/10), common (= 1/100 to < 1/10), uncommon (= 1/1,000 to < 1/100), rare (= 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Table 1 – Frequency of adverse reactions (MedDRA) in placebo-controlled Phase 3 studies System Organ Class Very common Common Uncommon Metabolism and nutrition disorders Decreased appetite, Hypertriglyceridaem ia Psychiatric disorders Abnormal dreams, Hallucination, Hallucination visual, Insomnia Anxiety, Depression, Hallucination auditory, Confusional state, Nightmare, Sleep disorder., Nervous system disorders Dyskinesia Dizziness, Headache, Somnolence Dysgeusia, Hyperkinesia, Syncope Eye disorders Dry eye Ear and labyrinth disorders Ear congestion Cardiac disorders Palpitations Vascular disorders Orthostatic Hypotension Hypertension, Hypotension Respiratory, thoracic and mediastinal disorders Dyspnoea Gastrointestinal disorders Constipation, Dry mouth, Nausea, Vomiting Abdominal distention, Abdominal pain, Abdominal pain upper, Dyspepsia Musculoskeletal and connective tissue disorders Muscle spasms Muscle twitching, Musculoskeletal stiffness, Myalgia, Pain in extremity Renal and urinary disorders Chromaturia, Nocturia Investigations Blood creatine phosphokinase increased Weight decreased Injury, poisoning and procedural complications Fall General disorders and administration site conditions Fatigue Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no known specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of opicapone by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Pharmacotherapeutic group: Anti-parkinson drugs, other dopaminergic agents, ATC code: N04BX04 Mechanism of action Opicapone is a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitor endowed with a high binding affinity (sub-picomolar) that translates into a slow complex dissociation rate constant and a long duration of action (>24 hours) in vivo. In the presence of a DOPA decarboxylase inhibitor (DDCI), COMT becomes the major metabolising enzyme for levodopa, catalysing its conversion to 3-O- methyldopa (3-OMD) in the brain and periphery. In patients taking levodopa and a peripheral DDCI, such as carbidopa or benserazide, opicapone increases levodopa plasma levels thereby improving the clinical response to levodopa. Pharmacodynamic effects Opicapone showed a marked (>90%) and long-lasting (>24 hours) COMT inhibition in healthy subjects after administration of 50 mg opicapone. At steady state, 50 mg opicapone significantly increased the extent of levodopa systemic exposure approximately 2 fold compared to placebo following a single oral administration of either 100/25 mg levodopa/carbidopa or 100/25 mg levodopa/benserazide administered 12 h after the opicapone dose. Clinical efficacy and safety The efficacy and safety of opicapone has been demonstrated in two Phase 3 double- blind, placebo and active (Study 1 only) controlled studies in 1,027 randomized adult patients with Parkinson’s disease treated with levodopa/DDCI (alone or in combination with other antiparkinsonian medicinal products) and end-of-dose motor fluctuations for up to 15 weeks. At screening, the mean age was similar in all treatment groups in both studies, ranging between 61.5 and 65.3 years. Patients had disease severity stages 1 to 3 (modified Hoehn and Yahr) at ON, were treated with 3 to 8 daily doses of levodopa/DDCI and had a daily average OFF-time of at least 1.5 hours. In both studies, 783 patients were treated with 25 mg or 50 mg of opicapone or placebo. In Study 1, 122 patients were treated with 5 mg of opicapone and 122 patients were treated with 200 mg of entacapone (active comparator). The majority of patients treated in both pivotal studies were treated with immediate- release levodopa/DDCI. There were 60 patients in the combined Phase 3 studies who were predominantly using controlled-release levodopa (i.e. >50% of their levodopa/DDCI formulations), 48 of whom were treated solely with controlled- release formulations of levodopa. Although there is no evidence that either the efficacy or safety of opicapone would be affected by use of controlled-release levodopa preparations, the experience with such preparations is limited. Opicapone demonstrated clinical efficacy superior to placebo during the double-blind treatment, both for the primary efficacy variable used in both pivotal studies, i.e. reduction in OFF-time (Table 2), the proportion of OFF-time responders (i.e. a subject who had a reduction in OFF-time of at least 1 hour from baseline to endpoint) (Table 3) and for most diary-derived secondary endpoints. The LS mean reduction in absolute OFF-time from baseline to endpoint in the entacapone group was -78.7 minutes. The difference in LS mean change in OFF-time of entacapone to placebo in Study 1 was -30.5 minutes. The difference in LS mean change in OFF-time of opicapone 50 mg to entacapone was -24.8 minutes and non- inferiority of opicapone 50 mg to entacapone was demonstrated (95% confidence interval: -61.4, 11.8). Table 2 Change in absolute OFF-time and ON-time (minutes) from baseline to endpoint Treatment N LS mean 95% CI p-value Study 1 Change in OFF-time Placebo 121 -48.3 -- -- OPC 5 mg 122 -77.6 -- -- OPC 25 mg 119 -73.2 -- -- OPC 50 mg 115 -103.6 -- -- OPC 5 mg – Placebo -- -29.3 -65.5, 6.8 0.0558 Treatment N LS mean 95% CI p-value OPC 25 mg – Placebo -- -25.0 -61.5, 11.6 0.0902 OPC 50 mg – Placebo -- -55.3 -92.0, -18.6 0.0016 Change in total ON-time without troublesome dyskinesiasa Placebo 121 40.0 -- -- OPC 5 mg 122 75.6 -- -- OPC 25 mg 119 78.6 -- -- OPC 50 mg 115 100.8 -- -- OPC 5 mg – Placebo -- 35.6 -2.5, 73.7 0.0670 OPC 25 mg – Placebo -- 38.6 0.2, 77.0 0.0489 OPC 50 mg – Placebo -- 60.8 22.1, 99.6 0.0021 Study 2 Change in OFF-time Placebo 136 -54.6 -- -- OPC 25 mg 125 -93.2 -- -- OPC 50 mg 150 -107.0 -- -- OPC 25 mg – placebo -- -38.5 -77.0, -0.1 0.0900 OPC 50 mg – placebo -- -52.4 -89.1, -15.7 0.0101 Change in total ON-time without troublesome dyskinesiasa Placebo 136 37.9 -- -- OPC 25 mg 125 79.7 -- -- OPC 50 mg 150 77.6 -- -- OPC 25 mg – placebo -- 41.8 0.7, 82.9 0.0839 OPC 50 mg – placebo -- 39.7 0.5, 78.8 0.0852 CI = confidence interval; LS mean = least square mean; N = number of non-missing values; OPC = opicapone. a. ON-time without troublesome dyskinesias=ON-time with non-troublesome dyskinesias + ON-time without dyskinesias Table 3 OFF-time responder rates at endpoint Response type Placebo (N=121) Entacapone (N=122) OPC 5 mg (N=122) OPC 25 mg (N=119) OPC 50 mg (N=115) Study 1 OFF-time reduction Responders, n (%) 55 (45.5) 66 (54.1) 64 (52.5) 66 (55.5) 75 (65.2) Difference to placebo p-value -- 0.1845 0.2851 0.1176 0.0036 (95% CI) (-0.039; 0.209) (-0.056; 0.193) (-0.025; 0.229) (0.065; 0.316) Study 2 OFF-time reduction Responders, n (%) 65 (47.8) NA NA 74 (59.2) 89 (59.3) Difference to placebo p-value -- -- -- 0.0506 0.0470 (95% CI) (0.001; 0.242) (0.003; 0.232) CI = confidence interval; N = total number of patients; n = number of patients with available information; NA = not applicable; OPC = opicapone Note: A responder was a patient who had a reduction of at least 1 hour in absolute OFF-time (OFF-time responder) The results of the open-label (OL) extension studies of 1 year duration in 862 patients who continued treatment from the double-blind studies (Study 1-OL and Study 2-OL) indicated maintenance of the effect achieved during DB study periods. In the OL studies, all patients began at a dose of 25 mg opicapone for the first week (7 days), regardless of their prior treatment in the double-blind period. If end-of-dose motor fluctuations were not sufficiently controlled and tolerability allowed, the opicapone dose could be increased to 50 mg. If unacceptable dopaminergic adverse events were seen, the levodopa dose was to be adjusted. If not sufficient to manage the adverse events, the opicapone dose could then be down titrated. For other adverse events, the levodopa and/or opicapone dose could be adjusted. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with opicapone in all subsets of the paediatric population with Parkinson’s disease and motor fluctuations (see section 4.2 for information on paediatric use).

Absorption Opicapone presents a low absorption (~20%). Pharmacokinetic results showed that opicapone is rapidly absorbed, with a tmax of 1.0 h to 2.5 h following once-daily multiple-dose administration up to 50 mg opicapone. Distribution In vitro studies over the opicapone concentration range 0.3 to 30 mcg/mL showed that binding of 14C-opicapone to human plasma proteins is high (99.9%) and concentration-independent. The binding of 14C-opicapone to plasma proteins was unaffected by the presence of warfarin, diazepam, digoxin and tolbutamide, and the binding of 14C-warfarin, 2-14C-diazepam, 3H-digoxin and 14C-tolbutamide was unaffected by the presence of opicapone and opicapone sulphate, the major human metabolite. After oral administration, the apparent volume of distribution of opicapone at a dose of 50 mg was 29 L with an inter-subject variability of 36%. Biotransformation Sulphation of opicapone appears to be the major metabolic pathway in humans, yielding the inactive opicapone sulphate metabolite. Other metabolic pathways include glucuronidation, methylation and reduction. The most abundant peaks in plasma after a single-dose of 100 mg 14C-opicapone are metabolites BIA 9-1103 (sulphate) and BIA 9-1104 (methylated), 67.1 and 20.5% of radioactive AUC respectively. Other metabolites were not found in quantifiable concentrations in the majority of plasma samples collected during a clinical mass balance study. The reduced metabolite of opicapone (found to be active in non-clinical studies) is a minor metabolite in human plasma and represented less than 10% of total systemic exposure to opicapone. In in vitro studies in human hepatic microsomes, minor inhibition of CYP1A2 and CYP2B6 was observed. All reductions in activity essentially occurred at the highest concentration of opicapone (10 mcg/mL). An in vitro study showed opicapone inhibited CYP2C8 activity. A single dose study with opicapone 25 mg showed an average increase of 30 % in the rate, but not the extent, of exposure to repaglinide (a CYP2C8 substrate), when the two drugs were co-administered. A second study conducted showed that, at steady state, opicapone 50 mg had no effect on repaglinide systemic exposure. Opicapone reduced CYP2C9 activity through competitive / mixed type mode of inhibition. However, clinical

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In rats, opicapone did not affect male and female fertility or prenatal development at exposure levels 22 times the therapeutic exposure in humans. In pregnant rabbits, opicapone was less well tolerated resulting in maximum systemic exposure levels around or below the therapeutic range. Although embryo-foetal development was not negatively influenced in rabbits, the study is not considered predictive for human risk assessment.

Capsule content Lactose monohydrate Sodium starch glycolate, Type A Maize starch, pregelatinized Magnesium stearate Capsule shell Gelatin Indigo carmine aluminium lake (E 132) Erythrosine (E 127) Titanium dioxide (E 171) Printing ink Shellac Titanium dioxide (E 171) Propylene glycol Ammonia solution, concentrated Simeticone

Not applicable.

HDPE bottles: 3 years Blisters: 5 years

This medicinal product does not require any special temperature storage conditions. Blisters: Store in the original blister in order to protect from moisture. HDPE bottles: Keep the bottle tightly closed in order to protect from moisture.

White high density polyethylene (HDPE) bottles with polypropylene (PP) child resistant closures containing 10, 30 or 90 capsules. OPA/Al/PVC//Al blisters containing 10, 30 or 90 capsules Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

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