ONGENTYS 50mg capsules medication leaflet

Each hard capsule contains 25 mg of opicapone.

Each hard capsule contains 171.9 mg of lactose (as monohydrate).

Each hard capsule contains 50 mg of opicapone.

Each hard capsule contains 148.2 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Light blue capsules, size 1, approximately 19 mm, imprinted “OPC 25” on the cap and “Bial” on thebody.

Dark blue capsules, size 1, approximately 19 mm, imprinted “OPC 50” on the cap and “Bial” on thebody.

Ongentys is indicated as adjunctive therapy to preparations of levodopa/ DOPA decarboxylaseinhibitors (DDCI) in adult patients with Parkinson’s disease and end-of-dose motor fluctuations whocannot be stabilised on those combinations.

The recommended dose is 50 mg of opicapone.

Ongentys should be taken once-daily at bedtime at least one hour before or after levodopacombinations.

Ongentys is to be administered as an adjunct to levodopa treatment and enhances the effects oflevodopa. Hence, it is often necessary to adjust levodopa dose by extending the dosing intervals and/orreducing the amount of levodopa per dose within the first days to first weeks after initiating thetreatment with opicapone according to the clinical condition of the patient (see section 4.4).

If one dose is missed, the next dose should be taken as scheduled. The patient should not take an extradose to make up for the missed dose.

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.

No dose adjustment is necessary in patients with renal impairment, as opicapone is not excreted by thekidney (see section 5.2).

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 section5.2).

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).

There is no relevant use of Ongentys in the paediatric population with Parkinson’s disease and motorfluctuations.

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 (seesection 4.5).

Ongentys is to be administered as an adjunct to levodopa treatment. Hence, the precautions valid forlevodopa treatment should also be taken into account for Ongentys. Opicapone enhances the effects oflevodopa. 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 oflevodopa by extending the dosing intervals and/or reducing the amount of levodopa per dose withinthe first days to first weeks after initiating treatment with Ongentys, according to the clinical conditionof the patient (see section 4.2).

If Ongentys is discontinued it is necessary to adjust the dosing of the other antiparkinsoniantreatments, especially levodopa, to achieve a sufficient level of control of the symptoms.

Patients and care-givers should be made aware that impulse control disorders including pathologicalgambling, increased libido, hypersexuality, compulsive spending or buying, binge eating andcompulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergictreatments. Patients should be monitored regularly for the development of impulse control disordersand review of treatment is recommended if such symptoms develop.

Increases in liver enzymes were reported in studies with nitrocatechol inhibitors of catechol-O-methyltransferase (COMT). For patients who experience progressive anorexia, asthenia and weightdecrease within a relatively short period of time, a general medical evaluation including liver functionshould be considered.

Ongentys contains lactose. Patients with rare hereditary problems of galactose intolerance, the totallactase 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’.

Combination of opicapone and MAO inhibitors could result in inhibition of the majority of thepathways responsible for the metabolism of catecholamines. Because of this, concomitant use ofopicapone with MAO inhibitors (e.g. phenelzine, tranylcypromine and moclobemide) other than thosefor 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 inbuccal absorption formulation), is permissible.

There is no experience with opicapone when used concomitantly with the MAO-B inhibitorsafinamide. Therefore, their concomitant use should be considered with appropriate caution.

Opicapone may interfere with the metabolism of medicinal products containing a catechol group thatare metabolised by COMT, e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine,dopexamine or dobutamine, leading to potentiated effects of these medicinal products. Carefulmonitoring of patients being treated with these medicinal products is advised when opicapone is used.

There is limited experience with opicapone when used concomitantly with tricyclic antidepressantsand noradrenaline re-uptake inhibitors (e.g. venlafaxine, maprotiline and desipramine). Thus, theirconcomitant use should be considered with appropriate caution.

A study conducted in healthy volunteers showed that when a single dose of 50 mg opicapone was co-administered (within 1 hour) with a single dose of quinidine (600 mg), systemic exposure ofopicapone decreased by 37% (AUC0-tlast). Thus, particular consideration should be given to caseswhere quinidine needs to be administered together with opicapone as their co-administration should beavoided.

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 nochanges in repaglinide’s exposure when repaglinide was administered following multiple once-dailyadministration of opicapone 50 mg.

There are no or limited amount of data from the use of opicapone in pregnant women. Opicaponecrossed the placenta in rats. Animal studies are insufficient with respect to reproductive toxicity (seesection 5.3). Ongentys is not recommended during pregnancy and in women of childbearing potentialnot using contraception.

Opicapone levels in the milk of lactating rats were equivalent to those in plasma. It is unknownwhether opicapone or its metabolites are excreted into human milk. A risk to the newborns/infantscannot be excluded. Breast-feeding should be discontinued during treatment with Ongentys.

The effects of opicapone on fertility in humans have not been studied. Animal studies with opicaponedo 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 usemachines. Opicapone may, together with levodopa, cause dizziness, symptomatic orthostatism andsomnolence. Therefore, caution should be exercised when driving or using machines.

The most common adverse reactions reported were nervous system disorders. Dyskinesia was the mostfrequently reported treatment-emergent adverse reaction (17.7%).

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 Decreased appetite,nutrition disorders Hypertriglyceridaemia

Psychiatric disorders Abnormal dreams, Anxiety,

Hallucination, Depression,

Hallucination visual, Hallucination auditory,

Insomnia Confusional state,

Nightmare,

Sleep disorder

Nervous system Dyskinesia Dizziness, Dysgeusia,disorders Headache, Hyperkinesia,

Somnolence Syncope

Eye disorders Dry eye

Ear and labyrinth Ear congestiondisorders

Cardiac disorders Palpitations

Vascular disorders Orthostatic Hypertension,

Hypotension Hypotension

Respiratory, thoracic Dyspnoeaand mediastinaldisorders

Gastrointestinal Constipation, Abdominal distention,disorders Dry mouth, Abdominal pain,

Nausea, Abdominal pain upper,

Vomiting Dyspepsia

Musculoskeletal and Muscle spasms Muscle twitching,connective tissue Musculoskeletaldisorders stiffness,

Myalgia,

Pain in extremity

Renal and urinary Chromaturia,disorders Nocturia

General disorders and Fatigueadministration siteconditions

Investigations Blood creatine Weight decreasedphosphokinaseincreased

Injury, poisoning and Fallproceduralcomplications

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Anti-parkinson drugs, other dopaminergic agents, ATC code: N04BX04

Opicapone is a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitorendowed with a high binding affinity (sub-picomolar) that translates into a slow complex dissociationrate constant and a long duration of action (>24 hours) in vivo.

In the presence of a DOPA decarboxylase inhibitor (DDCI), COMT becomes the major metabolisingenzyme for levodopa, catalysing its conversion to 3-O-methyldopa (3-OMD) in the brain andperiphery. 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.

Opicapone showed a marked (>90%) and long-lasting (>24 hours) COMT inhibition in healthysubjects after administration of 50 mg opicapone.

At steady state, 50 mg opicapone significantly increased the extent of levodopa systemic exposureapproximately 2 fold compared to placebo following a single oral administration of either 100/25 mglevodopa/carbidopa or 100/25 mg levodopa/benserazide administered 12 h after the opicapone dose.

The efficacy and safety of opicapone has been demonstrated in two Phase 3 double-blind, placebo andactive (Study 1 only) controlled studies in 1,027 randomized adult patients with Parkinson’s diseasetreated 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 alltreatment groups in both studies, ranging between 61.5 and 65.3 years. Patients had disease severitystages 1 to 3 (modified Hoehn and Yahr) at ON, were treated with 3 to 8 daily doses oflevodopa/DDCI and had a daily average OFF-time of at least 1.5 hours. In both studies, 783 patientswere treated with 25 mg or 50 mg of opicapone or placebo. In Study 1, 122 patients were treated with5 mg of opicapone and 122 patients were treated with 200 mg of entacapone (active comparator). Themajority of patients treated in both pivotal studies were treated with immediate-releaselevodopa/DDCI. There were 60 patients in the combined Phase 3 studies who were predominantlyusing controlled-release levodopa (i.e. >50% of their levodopa/DDCI formulations), 48 of whom weretreated solely with controlled-release formulations of levodopa. Although there is no evidence thateither the efficacy or safety of opicapone would be affected by use of controlled-release levodopapreparations, the experience with such preparations is limited.

Opicapone demonstrated clinical efficacy superior to placebo during the double-blind treatment, bothfor the primary efficacy variable used in both pivotal studies, i.e. reduction in OFF-time (Table 2), theproportion of OFF-time responders (i.e. a subject who had a reduction in OFF-time of at least 1 hourfrom 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 groupwas -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 toentacapone was -24.8 minutes and non-inferiority of opicapone 50 mg to entacapone wasdemonstrated (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

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 withoutdyskinesias

Table 3 - OFF-time responder rates at endpoint

Response type Placebo Entacapone OPC 5 mg OPC 25 mg OPC 50 mg(N=121) (N=122) (N=122) (N=119) (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 toplacebop-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 toplacebop-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-timeresponder)

The results of the open-label (OL) extension studies of 1 year duration in 862 patients who continuedtreatment from the double-blind studies (Study 1-OL and Study 2-OL) indicated maintenance of theeffect achieved during DB study periods. In the OL studies, all patients began at a dose of 25 mgopicapone for the first week (7 days), regardless of their prior treatment in the double-blind period. Ifend-of-dose motor fluctuations were not sufficiently controlled and tolerability allowed, the opicaponedose could be increased to 50 mg. If unacceptable dopaminergic adverse events were seen, thelevodopa dose was to be adjusted. If not sufficient to manage the adverse events, the opicapone dosecould then be down titrated. For other adverse events, the levodopa and/or opicapone dose could beadjusted.

The European Medicines Agency has waived the obligation to submit the results of studies withopicapone in all subsets of the paediatric population with Parkinson’s disease and motor fluctuations(see section 4.2 for information on paediatric use).

Opicapone presents a low absorption (~20%). Pharmacokinetic results showed that opicapone israpidly absorbed, with a tmax of 1.0 h to 2.5 h following once-daily multiple-dose administration up to50 mg opicapone.

In vitro studies over the opicapone concentration range 0.3 to 30 mcg/mL showed that binding of14C-opicapone to human plasma proteins is high (99.9%) and concentration-independent. The bindingof 14C-opicapone to plasma proteins was unaffected by the presence of warfarin, diazepam, digoxinand tolbutamide, and the binding of 14C-warfarin, 2-14C-diazepam, 3H-digoxin and 14C-tolbutamidewas 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 was29 L with an inter-subject variability of 36%.

Sulphation of opicapone appears to be the major metabolic pathway in humans, yielding the inactiveopicapone sulphate metabolite. Other metabolic pathways include glucuronidation, methylation andreduction.

The most abundant peaks in plasma after a single-dose of 100 mg 14C-opicapone are metabolites BIA9-1103 (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 samplescollected during a clinical mass balance study.

The reduced metabolite of opicapone (found to be active in non-clinical studies) is a minor metabolitein 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 wasobserved. 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 opicapone25 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 showedthat, 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 interaction studies conducted with warfarin showed no effect of opicapone on thepharmacodynamics of warfarin, a substrate of CYP2C9.

In healthy subjects, the opicapone elimination half-life (t1/2) was 0.7 h to 3.2 h following once-dailymultiple-dose administration up to 50 mg opicapone.

Following once-daily multiple oral doses of opicapone in the dose range of 5 to 50 mg, opicaponesulphate presented a long terminal phase with elimination half-life values ranging from 94 h to 122 hand, as a consequence of this long terminal elimination half-life, opicapone sulphate presented a highaccumulation ratio in plasma, with values close of up to 6.6.

After oral administration, the apparent total body clearance of opicapone at a dose of 50 mg was22 L/h, with an inter-subject variability of 45%.

Following administration of a single oral dose of 14C-opicapone, the main excretion route of opicaponeand its metabolites was faeces, accounting for 58.5% to 76.8% of the administered radioactivity (mean67.2%). The remainder of the radioactivity was excreted in urine (mean 12.8%) and via expired air(mean 15.9%). In urine, the primary metabolite was the glucuronide metabolite of opicapone, whileparent drug and other metabolites were generally below the limit of quantification. Overall, it can beconcluded that the kidney is not the primary route of excretion. Therefore, it can be presumed thatopicapone and its metabolites are mainly excreted in the faeces.

Opicapone exposure increased in a dose proportional manner following once-daily multiple doseadministration up to 50 mg opicapone.

In vitro studies have shown that opicapone is not transported by OATP1B1, but is transported by

OATP1B3, and efflux transported by P-gp and BCRP. BIA 9-1103, its major metabolite, wastransported by OATP1B1 and OATP1B3, and efflux transported by BCRP, but is not a substrate forthe P-gp/MDR1 efflux transporter.

At clinically relevant concentrations, opicapone is not expected to inhibit OAT1, OAT3, OATP1B1,

OATP1B3, OCT1, OCT2, BCRP, P-gp/MDR1, BSEP, MATE1 and MATE2-K transporters assuggested by in vitro and in vivo studies.

Elderly (≥ 65 years old)

The pharmacokinetics of opicapone was evaluated in elderly subjects (aged 65-78 years old) after 7-day multiple-dose administration of 30 mg. An increase in both the rate and extent of systemicexposure was observed for the elderly population when compared to the young population. The S-

COMT activity inhibition was significantly increased in elderly subjects. The magnitude of this effectis not considered to be of clinical relevance.

Weight

There is no relationship between exposure of opicapone and body weight over the range of 40-100 kg.

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh Class

B). The pharmacokinetics of opicapone was evaluated in healthy subjects and moderate chronichepatic impaired patients after administration of a single-dose of 50 mg. The bioavailability ofopicapone was significantly higher in patients with moderate chronic hepatic impairment and no safetyconcerns were observed. However, as opicapone is to be used as adjunctive levodopa-therapy, doseadjustments may be considered based on a potentially enhanced levodopa dopaminergic response andassociated tolerability. There is no clinical experience in patients with severe hepatic impairment(Child-Pugh Class C) (see section 4.2).

The pharmacokinetics of opicapone was not directly evaluated in subjects with chronic renalimpairment. However, an evaluation with 50 mg opicapone was performed in subjects included inboth phase 3 studies with GFR/1.73 m2 <60 mL/min (i.e. moderately decreased renal eliminationcapacity), and using pooled BIA 9-1103 data (major metabolite of opicapone). BIA 9-1103 plasmalevels were not affected in patients with chronic renal impairment, and as such, no dose adjustmentneeds to be considered.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In rats, opicapone did not affect male and female fertility or prenatal development at exposure levels22 times the therapeutic exposure in humans. In pregnant rabbits, opicapone was less well toleratedresulting in maximum systemic exposure levels around or below the therapeutic range. Althoughembryo-foetal development was not negatively influenced in rabbits, the study is not consideredpredictive for human risk assessment.

Lactose monohydrate

Sodium starch glycolate, Type A

Maize starch, pregelatinized

Magnesium stearate

Gelatin

Indigo carmine aluminium lake (E 132)

Erythrosine (E 127)

Titanium dioxide (E 171)

Shellac

Ammonia solution, concentrated

Indigo carmine aluminium lake (E 132)

Shellac

Titanium dioxide (E 171)

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 closurescontaining 10 or 30 capsules.

OPA/Al/PVC//Al blisters containing 10 or 30 capsules.

White high density polyethylene (HDPE) bottles with polypropylene (PP) child resistant closurescontaining 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 localrequirements.

Bial - Portela & Cª, S.A.

À Av. da Siderurgia Nacional4745-457 S. Mamede do Coronado

Portugal

Tel:+351 22 986 61 00

Fax: +351 22 986 61 90e-mail: info@bial.com

EU/1/15/1066/001-010

Date of first authorisation: 24 June 2016

Date of latest renewal: 18 February 2021

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.