USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) Avoid use in patients with end-stage renal disease. (8.6). Pregnancy: Based on animal data, may cause fetal harm (8.1) Avoid use in patients with end-stage renal disease. (8.6). 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of ONGENTYS in pregnant women. In animal studies, oral administration of opicapone during pregnancy resulted in adverse effects on embryofetal development (increased incidence of fetal abnormalities) at clinically relevant plasma exposures in one of two species tested. In addition, opicapone is always given concomitantly with levodopa/carbidopa, which is known to cause developmental toxicity in rabbits (s ee Data). The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively. The background risk for major birth defects and miscarriage in patients with Parkinsons disease is unknown.Data Animal Data Oral administration of opicapone (0, 150, 375, or 1000 mg/kg/day) to pregnant rats throughout gestation resulted in no adverse effects on embryofetal development. Plasma exposure (AUC) at the highest dose tested (1000 mg/kg/day) was approximately 40 times that in humans at the recommended human dose (50 mg/day). In pregnant rabbits, oral administration of opicapone (0, 100, 175, or 225 mg/kg/day) during the period of organogenesis resulted in increased incidence of structural abnormalities at all doses tested; maternal toxicity was observed at all but the lowest dose tested. no-effect dose for adverse effects on embryofetal development was not identified. Plasma exposure (AUC) at the low-effect dose (100 mg/kg/day) was less than that in humans at the RHD.Oral administration of opicapone (0, 150, 375, or 1000 mg/kg/day) throughout gestation and lactation resulted in no adverse effects on pre- and postnatal development; however, effects on neurobehavioral development in the offspring were not rigorously assessed. Plasma exposure (AUC) at the highest dose tested (1000 mg/kg/day) was approximately 40 times that in humans at the RHD.Opicapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The developmental toxicity of opicapone in combination with levodopa/carbidopa was not assessed in animals.. 8.2 Lactation Risk Summary There are no data on the presence of opicapone in human milk, the effects on the breastfed infant, or the effects on milk production. In lactating rats, oral administration of opicapone resulted in levels of opicapone or metabolites in milk similar to those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ONGENTYS and any potential adverse effects on the breastfed infant from ONGENTYS or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No dose adjustment is required for elderly patients. Of the total number of patients who received ONGENTYS 50 mg in Study and Study 2, 52% of patients were 65 years and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity to adverse reactions of some older individuals cannot be ruled out.. 8.6 Renal Impairment. The renal route of elimination plays minor role in the clearance of opicapone [see Clinical Pharmacology 12.3 )]. Avoid use of ONGENTYS in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min). No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. However, because of potential for increased exposure, monitor patients with severe renal impairment for adverse reactions and discontinue ONGENTYS if tolerability issues arise.. 8.7 Hepatic Impairment Opicapone exposure is increased in patients with hepatic impairment [see Clinical Pharmacology 12.3 )]. Avoid use of ONGENTYS in patients with severe (Child-Pugh C) hepatic impairment. Dosage adjustment is recommended for patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration 2.2 )]. No dosage adjustment is required in patients with mild (Child-Pugh A) hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT): May cause arrhythmias, increased heart rate, and excessive changes in blood pressure. Monitor patients when treated concomitantly with products metabolized by COMT. (4, 5.1) Falling Asleep During Activities of Daily Living: Advise patients prior to treatment. (5.2) Hypotension/Syncope: If occurs, consider discontinuing ONGENTYS or adjusting dosage of other medications that can lower blood pressure. (5.3) Dyskinesia: May cause or exacerbate dyskinesia; consider levodopa or dopaminergic medication dose reduction. (5.4) Hallucinations and Psychosis: Consider stopping ONGENTYS if occurs. (5.5) Impulse Control/Compulsive Disorders: Consider stopping ONGENTYS if occurs. (5.6) Withdrawal-Emergent Hyperpyrexia and Confusion: When discontinuing ONGENTYS, monitor patients and consider adjustment of other dopaminergic therapies as needed. (5.7) Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT): May cause arrhythmias, increased heart rate, and excessive changes in blood pressure. Monitor patients when treated concomitantly with products metabolized by COMT. (4, 5.1) Falling Asleep During Activities of Daily Living: Advise patients prior to treatment. (5.2) Hypotension/Syncope: If occurs, consider discontinuing ONGENTYS or adjusting dosage of other medications that can lower blood pressure. (5.3) Dyskinesia: May cause or exacerbate dyskinesia; consider levodopa or dopaminergic medication dose reduction. (5.4) Hallucinations and Psychosis: Consider stopping ONGENTYS if occurs. (5.5) Impulse Control/Compulsive Disorders: Consider stopping ONGENTYS if occurs. (5.6) Withdrawal-Emergent Hyperpyrexia and Confusion: When discontinuing ONGENTYS, monitor patients and consider adjustment of other dopaminergic therapies as needed. (5.7) 5.1 Cardiovascular Effects with Concomitant Use of Drugs Metabol ized by Catechol-O-Methyltransferase (COMT) Possible arrhythmias, increased heart rate, and excessive changes in blood pressure may occur with concomitant use of ONGENTYS and drugs metabolized by COMT (e.g., isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine), regardless of the route of administration (including inhalation). Monitor patients treated concomitantly with ONGENTYS and drugs metabolized by COMT [see Contraindications 4 ), Drug Interactions 7.1 7.2 )].. 5.2 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with dopaminergic medications and medications that increase levodopa exposure, including ONGENTYS, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Before initiating treatment with ONGENTYS, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with dopaminergic therapy, such as concomitant sedating medications or the presence of sleep disorder. If patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving motor vehicle, conversations, eating), consider discontinuing ONGENTYS or adjusting other dopaminergic or sedating medications. If decision is made to continue ONGENTYS, patients should be advised not to drive and to avoid other potentially dangerous activities. 5.3 Hypotension/Syncope In Study and Study [see Clinical Studies 14 )], hypotension (orthostatic and non-orthostatic), syncope, and presyncope occurred in 5% of patients treated with ONGENTYS 50 mg compared to 1% of patients who received placebo. Monitor patients for hypotension (orthostatic and non-orthostatic) and advise patients about the risk for syncope and presyncope. If these adverse reactions occur, consider discontinuing ONGENTYS or adjusting the dosage of other medications that can lower blood pressure.. 5.4 Dyskinesia ONGENTYS potentiates the effects of levodopa [see Clinical Pharmacology 12.3 )] and may cause dyskinesia or exacerbate pre-existing dyskinesia.In controlled clinical trials (Study and Study 2) [see Clinical Studies 14 )], dyskinesia occurred in 20% of patients treated with ONGENTYS 50 mg compared to 6% of patients who received placebo. Dyskinesia was also the most common adverse reaction leading to discontinuation of ONGENTYS [see Adverse Reactions 6.1 )]. Reducing the patients daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia that occurs during treatment with ONGENTYS.. 5.5 Hallucinations and Psychosis In Study and Study 2, hallucinations (hallucinations, auditory hallucinations, visual hallucinations, mixed hallucinations) occurred in 3% of patients treated with ONGENTYS 50 mg compared to 1% of patients who received placebo. Delusions, agitation, or aggressive behavior occurred in 1% of patients treated with ONGENTYS 50 mg, and in no patient who received placebo. Consider stopping ONGENTYS if hallucinations or psychotic-like behaviors occur.Patients with major psychotic disorder should ordinarily not be treated with ONGENTYS because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of PD. 5.6 Impulse Control Compulsive Disorders Patients treated with ONGENTYS can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more dopaminergic therapies that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with ONGENTYS. In Study and Study 2, impulse control disorders occurred in 1% of patients treated with ONGENTYS 50 mg, and in no patient who received placebo. Re-evaluate the patients current therapy(ies) for Parkinsons disease and consider stopping ONGENTYS if patient develops such urges while taking ONGENTYS.Use with caution in Parkinsons patients with suspected or diagnosed dopamine dysregulation syndrome.. 5.7 Withdrawal- mergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. In the controlled clinical studies of ONGENTYS, patients discontinued ONGENTYS treatment without dose tapering or gradual withdrawal. There were no reports of neuroleptic malignant syndrome in ONGENTYS controlled clinical studies. When discontinuing ONGENTYS, monitor patients and consider adjustment of other dopaminergic therapies as needed [see Dosage and Administration 2.3 )].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT) [see Warnings and Precautions 5.1 )] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions 5.2 )] Hypotension/Syncope [see Warnings and Precautions 5.3 )] Dyskinesia [see Warnings and Precautions 5.4 )] Hallucinations and Psychosis [see Warnings and Precautions 5.5 )] Impulse Control/Compulsive Disorders [see Warnings and Precautions 5.6 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions 5.7 )] Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT) [see Warnings and Precautions 5.1 )] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions 5.2 )] Hypotension/Syncope [see Warnings and Precautions 5.3 )] Dyskinesia [see Warnings and Precautions 5.4 )] Hallucinations and Psychosis [see Warnings and Precautions 5.5 )] Impulse Control/Compulsive Disorders [see Warnings and Precautions 5.6 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions 5.7 )] Most common adverse reactions (>=4% and placebo): dyskinesia, constipation, blood creatine kinase increased, hypotension/syncope, and weight decreased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of ONGENTYS was evaluated in 265 patients with Parkinsons disease (PD) in two 14-15 week placebo- and active-controlled (Study 1) or placebo-controlled (Study 2) studies [see Clinical Studies 14 )]. All patients were taking stable dose of levodopa and DOPA decarboxylase inhibitor, alone or in combination with other PD medications. In Study and Study 2, the mean age of patients was 63.6 years, 59% of patients were male, and 89% of patients were Caucasian. At baseline, the mean duration of PD was 7.6 years. Adverse Reactions Leading to Discontinuation of Treatment In Study and Study 2, total of 8% of ONGENTYS 50 mg-treated patients and 6% of patients who received placebo discontinued due to adverse events. The most common adverse reaction leading to discontinuation was dyskinesia, reported in 3% of ONGENTYS 50 mg-treated patients and 0.4% of patients who received placebo. Common Adverse ReactionsAdverse reactions that occurred in the pooled studies at an incidence of at least 2% and greater than placebo are presented in Table 1. The most common adverse reactions (incidence at least 4% and greater than placebo) were dyskinesia, constipation, blood creatine kinase increased, hypotension/syncope, and weight decreased. Table 1: Adverse Reactions with an Incidence of at Least % in Patients Treated with ONGENTYS and Greater than on Placebo, in Pooled Study and Study Adverse ReactionsONGENTYS 50 mgN=265%Placebo N=257%Nervous system disordersDyskinesiaDizziness20361Gastrointestinal disordersConstipationDry mouth6321Psychiatric disordersHallucination1Insomnia3312InvestigationsBlood creatine kinase increasedWeight decreased5420Vascular disordersHypotension/syncope2Hypertension53121 Includes hallucinations, hallucinations visual, hallucinations auditory, and hallucinations mixed2 Includes hypotension, orthostatic hypotension, syncope, and presyncope.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Opicapone is selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD). 12.2 Pharmacodynamics COMT Activity Once-daily administration of ONGENTYS 50 mg caused inhibition of COMT activity in erythrocytes; the maximal inhibition seen was 84% and was maintained >65% over 24-hour dosing interval in patients with Parkinsons disease. Following termination of treatment, COMT inhibition slowly returns to baseline levels, with >35% inhibition still observed days after the last dose. Effects on Levodopa Peak (Cmax) and overall levodopa exposure (AUC) increased by 43-44% and 62-94%, respectively, in PD patients following once-daily administration of ONGENTYS at bedtime with levodopa/carbidopa administered every three or every four hours, as compared to after administration of levodopa/carbidopa alone. Cardiac ElectrophysiologyAt dose 16 times the recommended dosage, ONGENTYS does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics Opicapone demonstrates dose-proportional pharmacokinetics over 25 mg (0.5 times the recommended dosage) to 50 mg dose range. The pharmacokinetics of opicapone are similar in both PD patients and healthy subjects. AbsorptionAfter single-dose administration of ONGENTYS 50 mg, the median (range) plasma Tmax value was 2.0 (1.0-4.0) hours.Effect of FoodFollowing moderate fat/moderate calorie meal, the mean peak plasma concentration (Cmax) for opicapone decreased 62%, the mean overall plasma exposure (AUC) decreased 31%, and the Tmax was delayed by hours. In Study 1, ONGENTYS was administered without regard to food. In Study 2, ONGENTYS administration and food consumption were separated by hour [see Dosage and Administration 2.1 ), Clinical Studies 14 )]. DistributionOpicapone is highly bound to plasma proteins (>99%), which is independent of concentration. EliminationThe mean elimination half-life of opicapone is to hours. MetabolismSulphation is the primary metabolic pathway of opicapone, based on clinical studies and in vitro assessments. Other metabolic pathways include glucuronidation, methylation (by COMT), reduction, and glutathione conjugation. ExcretionAfter administration of single dose of radiolabeled opicapone 100 mg (2 times the recommended dosage) to healthy subjects, approximately 70% of the dose was recovered in feces (22% as unchanged), 20% in expired air, and 5% in urine (<1% as unchanged). Specific PopulationsNo clinically significant differences in the pharmacokinetics of opicapone were observed based on age (i.e., 18 to 40 years of age and >= 65 years of age), sex, or race/ethnicity (i.e., Japanese, Caucasian, Asian, and Black). Renal ImpairmentBased on population pharmacokinetic analyses, no clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild or moderate renal impairment (CLcr 30-89 mL/min using the Cockcroft-Gault equation) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (CLcr <30 mL/min) have not been studied [see Use in Specific Populations 8.6 )] Hepatic ImpairmentThe single-dose pharmacokinetics of opicapone was evaluated in subjects with mild (Child-Pugh: A) and moderate (Child-Pugh: B) hepatic impairment. In subjects with mild hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 35%, which is not expected to be clinically significant. In subjects with moderate hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 84%. Dosage adjustment for ONGENTYS is required in subjects with moderate hepatic impairment [see Dosage and Administration 2.2 )]. ONGENTYS has not been studied in patients with severe hepatic impairment (Child-Pugh: C) [see Use in Speci fic Populations 8.7 )]. Drug Interaction StudiesClinical StudiesNo clinically significant differences in the pharmacokinetics of opicapone were observed when administered concomitantly with quinidine (index substrate of P-gp [MDR1]), acetaminophen, or rasagiline.No clinically significant differences in the pharmacokinetics of the following drugs were observed when administered concomitantly with opicapone: S-warfarin (index substrate of CYP2C9), R-Warfarin (substrate of CYP1A2 and CYP3A4), or repaglinide (index substrate of CYP2C8 and OATP1B1). No clinically significant differences in the pharmacokinetics of the following drugs for the treatment of Parkinsons disease were observed when administered concomitantly with opicapone: rasagiline, selegiline, pramipexole, ropinirole, or amantadine.In Vitro StudiesOpicapone does not affect protein binding of warfarin, diazepam, digoxin, or tolbutamide, in vitro. CYP Enzymes: Opicapone is not an inhibitor or inducer of major CYPs. Transporter Systems: Opicapone is substrate of P-gp (MDR1) (see Clinical Studies), BCRP, MRP2, OATP1B3, and OATP2B1. No clinically significant transporter mediated interaction is expected for opicapone. Opicapone is not an inhibitor of P-gp (MDR1), BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B3, BSEP, MATE1, or MATE2-K.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of ONGENTYS for the adjunctive treatment to levodopa/carbidopa in patients with Parkinsons disease (PD) experiencing off episodes was evaluated in two double-blind, randomized, parallel-group, placebo- and active-controlled (Study 1, NCT01568073), or placebo-controlled (Study 2, NCT01227655) studies of 14-15 week duration. All patients were treated with levodopa/ DOPA decarboxylase inhibitor (DDCI) (alone or in combination with other PD medications). The double-blind period for each study began with period for levodopa/DDCI dose adjustment (up to weeks), followed by stable maintenance period of 12 weeks. Study 1In Study 1, patients (n=600) were randomized to treatment with one of doses of ONGENTYS. The intention to treat (ITT) population included patients treated with ONGENTYS 50 mg once daily (n=115) or placebo (n=120). Baseline demographic characteristics were similar across all treatment groups: approximately 60% of patients were male, mean age was 64 years, and all patients were Caucasian. Baseline PD characteristics in the treatment groups were: mean duration of PD of years for ONGENTYS 50 mg compared to 7.7 years for placebo, and mean onset of motor fluctuations of 2.2 years prior to study enrollment. Eighty-two percent of patients in both groups used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (68%), amantadine (23%), MAO-B inhibitors (20%), and anticholinergics (5%). The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed days prior to each of the scheduled visits. ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo (Table 2). Table 2: Study - Absolute OFF-time (Hours) Change from Baseline to Endpoint NBaselineMean (SE)LS Mean Change from Baseline (SE)Placebo-subtracted Difference (95% CI)Adjusted p-value Placebo 1206.17 hours(0.162)-0.93(0.223)----ONGENTYS 50 mg 1156.20 hours(0.166)-1.95(0.233)-1.01(-1.620, -0.407)p=0.002CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error. Adjusted values were calculated using gatekeeping procedure controlling for multiplicity.ON-time without troublesome dyskinesia was secondary efficacy endpoint in Study (Table 3). Table 3: Study - Absolute ON-time Without Troublesome Dyskinesia (Hours) Change from Baseline to Endpoint NBaselineMean (SE)LS Mean Change from Baseline (SE)Placebo-subtracted Difference (95% CI)Nominal p-value Placebo 1209.61 (0.191)0.75(0.237)----ONGENTYS 50 mg 1159.54(0.183)1.84(0.247)1.08(0.440, 1.728)p=0.001CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error. Unadjusted p-value.Study 2In Study 2, patients (n=427) were randomized to treatment with either one of two doses of ONGENTYS once daily (n=283) or placebo (n=144). The intention to treat (ITT) study population included patients treated with ONGENTYS 50 mg once daily (n=147) or placebo (n=135). Baseline demographic characteristics (ONGENTYS 50 mg vs. placebo) were: mean age (66 years vs. 62 years), male (61% vs. 53%), Caucasian (78% vs. 66%) and Asian (21% vs. 31%). Baseline PD characteristics were generally similar across treatment groups with mean duration of PD of 8.2 years, and mean onset of motor fluctuations of 3.2 years prior to study enrollment. Eighty-five percent of patients treated with ONGENTYS 50 mg compared to 81% of patients who received placebo used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (70%), amantadine (21%), MAO-B inhibitors (20%), and anticholinergics (12%). The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed days prior to each of the scheduled visits. ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo (Table 4). Table 4: Study - Absolute OFF-time (Hours) Change from Baseline to EndpointNBaselineMean (SE)LS Mean Change from Baseline (SE)Placebo-subtracted Difference (95% CI) Adjusted p-value Placebo 1356.12(0.200)-1.07(0.239)---- ONGENTYS 50 mg 1476.32(0.183)-1.98(0.230)-0.91(-1.523, -0.287)p=0.008CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error. Adjusted values were calculated using Dunnetts alpha level adjustment to control for multiplicity.ON-time without troublesome dyskinesia was secondary efficacy endpoint in Study (Table 5). Table 5: Study - Absolute ON-time without troublesome dyskinesia (Hours) Change from Baseline to EndpointNBaselineMean (SE)LS Mean Change from Baseline (SE)Placebo-subtracted Difference (95% CI) Nominal p-value Placebo 1359.61(0.206)0.80(0.256)---- ONGENTYS 50 mg 1479.37(0.183)1.43(0.247)0.62(-0.039, 1.287)p=0.065 (NS)CI=confidence interval; LS =least squares; N=total number of patients; SE=standard error.= not statistically significant.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of ONGENTYS was evaluated in 265 patients with Parkinsons disease (PD) in two 14-15 week placebo- and active-controlled (Study 1) or placebo-controlled (Study 2) studies [see Clinical Studies 14 )]. All patients were taking stable dose of levodopa and DOPA decarboxylase inhibitor, alone or in combination with other PD medications. In Study and Study 2, the mean age of patients was 63.6 years, 59% of patients were male, and 89% of patients were Caucasian. At baseline, the mean duration of PD was 7.6 years. Adverse Reactions Leading to Discontinuation of Treatment In Study and Study 2, total of 8% of ONGENTYS 50 mg-treated patients and 6% of patients who received placebo discontinued due to adverse events. The most common adverse reaction leading to discontinuation was dyskinesia, reported in 3% of ONGENTYS 50 mg-treated patients and 0.4% of patients who received placebo. Common Adverse ReactionsAdverse reactions that occurred in the pooled studies at an incidence of at least 2% and greater than placebo are presented in Table 1. The most common adverse reactions (incidence at least 4% and greater than placebo) were dyskinesia, constipation, blood creatine kinase increased, hypotension/syncope, and weight decreased. Table 1: Adverse Reactions with an Incidence of at Least % in Patients Treated with ONGENTYS and Greater than on Placebo, in Pooled Study and Study Adverse ReactionsONGENTYS 50 mgN=265%Placebo N=257%Nervous system disordersDyskinesiaDizziness20361Gastrointestinal disordersConstipationDry mouth6321Psychiatric disordersHallucination1Insomnia3312InvestigationsBlood creatine kinase increasedWeight decreased5420Vascular disordersHypotension/syncope2Hypertension53121 Includes hallucinations, hallucinations visual, hallucinations auditory, and hallucinations mixed2 Includes hypotension, orthostatic hypotension, syncope, and presyncope.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).AdministrationInstruct patients and/or caregivers that ONGENTYS capsules should be taken at bedtime. Inform patients to not eat food for hour before and for at least hour after intake of ONGENTYS [see Dosage and Administration 2.1 )]. Concomitant MedicationsCertain medications can cause an interaction with ONGENTYS. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines, dietary supplements, and herbal products [see Warnings and Precautions 5.1 and Drug Interactions 7 )].Falling Asleep During Activities of Daily LivingAdvise patients and/or caregivers that somnolence has been reported with ONGENTYS. Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living. These adverse reactions may affect some patients ability to drive and operate machinery safely [see Warnings and Precautions 5.2 )].Hypotension/SyncopeAdvise patients that ONGENTYS may cause hypotension or syncope [see Warnings and Precautions 5.3 )]. Dyskinesia Advise patients that ONGENTYS may cause dyskinesia or exacerbate pre-existing dyskinesia [see Warnings and Precautions 5.4 )]. Hallucinations and Psychosis Advise patients that ONGENTYS may cause hallucinations, delusions, or aggressive behavior and they should report any of these adverse reactions to their healthcare provider [see Warnings and Precautions 5.5 )]. Impulse Control/Compulsive DisordersInform patients of the potential for experiencing intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and other intense urges and the inability to control these urges while taking ONGENTYS and one or more medications that increase central dopaminergic tone that are generally used for the treatment of PD. Advise patients that they should report any of these adverse reactions to their healthcare provider [see Warnings and Precautions 5.6 )].Withdrawal-Emergent Hyperpyrexia and ConfusionAdvise patients to contact their healthcare provider before stopping ONGENTYS. Tell patients to inform their healthcare provider if they develop symptoms such as fever, confusion, or severe muscle stiffness after stopping ONGENTYS [see Warnings and Precautions 5.7 )].For further information on ONGENTYS, call 1-833-ONGENTYS (833-664-3689) or visit www.ongentys.comDistributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130Under license from BIAL-Portela Ca, S.A. ONGENTYS is registered trademark of BIAL-Portela Ca, S.A.91067001.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Opicapone demonstrates dose-proportional pharmacokinetics over 25 mg (0.5 times the recommended dosage) to 50 mg dose range. The pharmacokinetics of opicapone are similar in both PD patients and healthy subjects. AbsorptionAfter single-dose administration of ONGENTYS 50 mg, the median (range) plasma Tmax value was 2.0 (1.0-4.0) hours.Effect of FoodFollowing moderate fat/moderate calorie meal, the mean peak plasma concentration (Cmax) for opicapone decreased 62%, the mean overall plasma exposure (AUC) decreased 31%, and the Tmax was delayed by hours. In Study 1, ONGENTYS was administered without regard to food. In Study 2, ONGENTYS administration and food consumption were separated by hour [see Dosage and Administration 2.1 ), Clinical Studies 14 )]. DistributionOpicapone is highly bound to plasma proteins (>99%), which is independent of concentration. EliminationThe mean elimination half-life of opicapone is to hours. MetabolismSulphation is the primary metabolic pathway of opicapone, based on clinical studies and in vitro assessments. Other metabolic pathways include glucuronidation, methylation (by COMT), reduction, and glutathione conjugation. ExcretionAfter administration of single dose of radiolabeled opicapone 100 mg (2 times the recommended dosage) to healthy subjects, approximately 70% of the dose was recovered in feces (22% as unchanged), 20% in expired air, and 5% in urine (<1% as unchanged). Specific PopulationsNo clinically significant differences in the pharmacokinetics of opicapone were observed based on age (i.e., 18 to 40 years of age and >= 65 years of age), sex, or race/ethnicity (i.e., Japanese, Caucasian, Asian, and Black). Renal ImpairmentBased on population pharmacokinetic analyses, no clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild or moderate renal impairment (CLcr 30-89 mL/min using the Cockcroft-Gault equation) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (CLcr <30 mL/min) have not been studied [see Use in Specific Populations 8.6 )] Hepatic ImpairmentThe single-dose pharmacokinetics of opicapone was evaluated in subjects with mild (Child-Pugh: A) and moderate (Child-Pugh: B) hepatic impairment. In subjects with mild hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 35%, which is not expected to be clinically significant. In subjects with moderate hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 84%. Dosage adjustment for ONGENTYS is required in subjects with moderate hepatic impairment [see Dosage and Administration 2.2 )]. ONGENTYS has not been studied in patients with severe hepatic impairment (Child-Pugh: C) [see Use in Speci fic Populations 8.7 )]. Drug Interaction StudiesClinical StudiesNo clinically significant differences in the pharmacokinetics of opicapone were observed when administered concomitantly with quinidine (index substrate of P-gp [MDR1]), acetaminophen, or rasagiline.No clinically significant differences in the pharmacokinetics of the following drugs were observed when administered concomitantly with opicapone: S-warfarin (index substrate of CYP2C9), R-Warfarin (substrate of CYP1A2 and CYP3A4), or repaglinide (index substrate of CYP2C8 and OATP1B1). No clinically significant differences in the pharmacokinetics of the following drugs for the treatment of Parkinsons disease were observed when administered concomitantly with opicapone: rasagiline, selegiline, pramipexole, ropinirole, or amantadine.In Vitro StudiesOpicapone does not affect protein binding of warfarin, diazepam, digoxin, or tolbutamide, in vitro. CYP Enzymes: Opicapone is not an inhibitor or inducer of major CYPs. Transporter Systems: Opicapone is substrate of P-gp (MDR1) (see Clinical Studies), BCRP, MRP2, OATP1B3, and OATP2B1. No clinically significant transporter mediated interaction is expected for opicapone. Opicapone is not an inhibitor of P-gp (MDR1), BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B3, BSEP, MATE1, or MATE2-K.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of ONGENTYS in pregnant women. In animal studies, oral administration of opicapone during pregnancy resulted in adverse effects on embryofetal development (increased incidence of fetal abnormalities) at clinically relevant plasma exposures in one of two species tested. In addition, opicapone is always given concomitantly with levodopa/carbidopa, which is known to cause developmental toxicity in rabbits (s ee Data). The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively. The background risk for major birth defects and miscarriage in patients with Parkinsons disease is unknown.Data Animal Data Oral administration of opicapone (0, 150, 375, or 1000 mg/kg/day) to pregnant rats throughout gestation resulted in no adverse effects on embryofetal development. Plasma exposure (AUC) at the highest dose tested (1000 mg/kg/day) was approximately 40 times that in humans at the recommended human dose (50 mg/day). In pregnant rabbits, oral administration of opicapone (0, 100, 175, or 225 mg/kg/day) during the period of organogenesis resulted in increased incidence of structural abnormalities at all doses tested; maternal toxicity was observed at all but the lowest dose tested. no-effect dose for adverse effects on embryofetal development was not identified. Plasma exposure (AUC) at the low-effect dose (100 mg/kg/day) was less than that in humans at the RHD.Oral administration of opicapone (0, 150, 375, or 1000 mg/kg/day) throughout gestation and lactation resulted in no adverse effects on pre- and postnatal development; however, effects on neurobehavioral development in the offspring were not rigorously assessed. Plasma exposure (AUC) at the highest dose tested (1000 mg/kg/day) was approximately 40 times that in humans at the RHD.Opicapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The developmental toxicity of opicapone in combination with levodopa/carbidopa was not assessed in animals.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONONGENTYS(R) (on-JEN-tis)(opicapone) capsulesWhat is ONGENTYSONGENTYS is prescription medicine used with levodopa and carbidopa in people with Parkinsons disease (PD) who are having OFF episodes.It is not known if ONGENTYS is safe and effective in children.Do not take ONGENTYS if you:take type of medicine called non-selective monoamine-oxidase (MAO) inhibitor, such as phenelzine, isocarboxazid, or tranylcypromine. Ask your healthcare provider or pharmacist if you are taking non-selective MAO inhibitor. have tumor that secretes hormones known as catecholamines. These tumors include pheochromocytoma (a type of adrenal gland tumor) and paraganglioma.Before taking ONGENTYS, tell your healthcare provider about all of your medical conditions, including if you:have daytime sleepiness from sleep disorder, have unexpected or unpredictable periods of sleep or sleepiness, take medicine to help you sleep, or take any medicine that makes you feel sleepy. have or have had intense urges or unusual behaviors, including gambling, increased sex drive, binge eating, or compulsive shopping. have history of uncontrolled sudden movements (dyskinesia). have or have had hallucinations or psychosis. have liver problems. have kidney problems. are pregnant or plan to become pregnant. It is not known if ONGENTYS will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ONGENTYS passes into breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ONGENTYS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take nonselective MAO inhibitors (such as phenelzine, tranylcypromine, and isocarboxazid) or catecholamine medicines (such as isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine), regardless of how you take the medicine (by mouth, inhaled, or by injection). ONGENTYS and other medicines may affect each other causing side effects. ONGENTYS may affect the way other medicines work, and other medicines may affect how ONGENTYS works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take ONGENTYSo Take ONGENTYS exactly as your healthcare provider tells you to. ONGENTYS should be taken time each day at bedtime. Do not eat hour before taking ONGENTYS and do not eat for at least hour after taking ONGENTYS.o If you miss dose, take your usual dose of ONGENTYS on the next day at bedtime. Do not stop taking ONGENTYS or change your dose before talking to your healthcare provider. Your dose of other Parkinsons disease medicines may change when stopping ONGENTYS. Tell your healthcare provider if you have symptoms of withdrawal such as fever, confusion, or severe muscle stiffness.o If you take too much ONGENTYS, call your healthcare provider or Poison Control Center at 1-800-222-1222, or go to the nearest hospital emergency room right away.What should avoid while taking ONGENTYS Do not drive, operate machinery, or do other dangerous activities until you know how ONGENTYS affects you.What are the possible side effects of ONGENTYSONGENTYS may cause serious side effects, including: Falling asleep during normal activities. You may suddenly fall asleep while doing normal activities such as driving car, talking or eating while taking ONGENTYS or other medicines used to treat Parkinsons disease, without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking ONGENTYS are higher if you take other medicines that cause drowsiness. Low blood pressure or dizziness. Low blood pressure, dizziness, light headedness, or fainting can happen with ONGENTYS. Tell your healthcare provider if you become dizzy, lightheaded, or faint while taking ONGENTYS. Uncontrolled sudden movements (dyskinesia). ONGENTYS may cause uncontrolled sudden movements or make such movements you already have worse or happen more often. Tell your healthcare provider if this happens. Seeing, hearing, believing, or feeling things that are not real or not true. Taking ONGENTYS may cause seeing, hearing, or feeling things that are not real (hallucinations), believing things that are not real (delusions), or aggressive behavior. Tell your healthcare provider if you have any of these changes in your behavior. Unusual urges (impulse control and compulsive disorders). Some people taking ONGENTYS may get urges to behave in way unusual for them. Examples of this are unusual urges to gamble, increased sexual urges, strong urges to spend money, binge eating, and the inability to control these urges. If you or your family notice that you are developing any unusual behaviors, talk to your healthcare provider.Tell your healthcare provider if you experience any of these side effects.The most common side effects of ONGENTYS include: uncontrolled sudden movements (dyskinesia) constipation increase in certain enzyme called blood creatine kinaselow blood pressure weight lossThese are not all of the possible side effects of ONGENTYS. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ONGENTYSStore ONGENTYS at temperature below 86F (30C). Keep ONGENTYS and all medicines out of the reach of children.General information about the safe and effective use of ONGENTYS. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ONGENTYS for condition for which it was not prescribed. Do not give ONGENTYS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ONGENTYS that is written for health professionals.What are the ingredients in ONGENTYS Active ingredient: opicaponeInactive ingredients: lactose, magnesium stearate, pregelatinized starch, and sodium starch glycolate. The capsule shells contain: FD&C Blue2, FD&C Red3, gelatin, and titanium dioxide.Distributed by: Neurocrine Biosciences, Inc. San Diego, CA 92130Under license from BIAL-Portela Ca, S.A. ONGENTYS is registered trademark of BIAL-Portela Ca, S.A. For more information, go to www.ongentys.com or call 1-833-664-3689. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 4/2020. take type of medicine called non-selective monoamine-oxidase (MAO) inhibitor, such as phenelzine, isocarboxazid, or tranylcypromine. Ask your healthcare provider or pharmacist if you are taking non-selective MAO inhibitor. have tumor that secretes hormones known as catecholamines. These tumors include pheochromocytoma (a type of adrenal gland tumor) and paraganglioma.. have daytime sleepiness from sleep disorder, have unexpected or unpredictable periods of sleep or sleepiness, take medicine to help you sleep, or take any medicine that makes you feel sleepy. have or have had intense urges or unusual behaviors, including gambling, increased sex drive, binge eating, or compulsive shopping. have history of uncontrolled sudden movements (dyskinesia). have or have had hallucinations or psychosis. have liver problems. have kidney problems. are pregnant or plan to become pregnant. It is not known if ONGENTYS will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ONGENTYS passes into breast milk. You and your healthcare provider should decide the best way to feed your baby if you take ONGENTYS. Do not drive, operate machinery, or do other dangerous activities until you know how ONGENTYS affects you.. Falling asleep during normal activities. You may suddenly fall asleep while doing normal activities such as driving car, talking or eating while taking ONGENTYS or other medicines used to treat Parkinsons disease, without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking ONGENTYS are higher if you take other medicines that cause drowsiness. Low blood pressure or dizziness. Low blood pressure, dizziness, light headedness, or fainting can happen with ONGENTYS. Tell your healthcare provider if you become dizzy, lightheaded, or faint while taking ONGENTYS. Uncontrolled sudden movements (dyskinesia). ONGENTYS may cause uncontrolled sudden movements or make such movements you already have worse or happen more often. Tell your healthcare provider if this happens. Seeing, hearing, believing, or feeling things that are not real or not true. Taking ONGENTYS may cause seeing, hearing, or feeling things that are not real (hallucinations), believing things that are not real (delusions), or aggressive behavior. Tell your healthcare provider if you have any of these changes in your behavior. Unusual urges (impulse control and compulsive disorders). Some people taking ONGENTYS may get urges to behave in way unusual for them. Examples of this are unusual urges to gamble, increased sexual urges, strong urges to spend money, binge eating, and the inability to control these urges. If you or your family notice that you are developing any unusual behaviors, talk to your healthcare provider.. uncontrolled sudden movements (dyskinesia) constipation increase in certain enzyme called blood creatine kinase. low blood pressure weight loss. Store ONGENTYS at temperature below 86F (30C). Keep ONGENTYS and all medicines out of the reach of children.