ONGENTYS

1 INDICATIONS AND USAGE ONGENTYS is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. ONGENTYS is a catechol-O-methyltransferase (COMT) inhibitor indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage is 50 mg administered orally once daily at bedtime. ( 2.1 ) Patients should not eat food for 1 hour before and for at least 1 hour after intake of ONGENTYS. ( 2.1 ) The recommended dosage in patients with moderate hepatic impairment is 25 mg orally once daily at bedtime; avoid use in patients with severe hepatic impairment. ( 2.2 ) 2.1 Dosing and Administration Information The recommended dosage of ONGENTYS is 50 mg administered orally once daily at bedtime. Patients should not eat food for 1 hour before and for at least 1 hour after intake of ONGENTYS [see Clinical Pharmacology ( 12.3 )]. 2.2 Dosage Recommendations for Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh B), the recommended dose of ONGENTYS is 25 mg orally once daily at bedtime [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. Avoid use of ONGENTYS in patients with severe (Child-Pugh C) hepatic impairment [ see Use in Specific Populations ( 8.7 ) , Clinical Pharmacology ( 12.3 ) ]. 2.3 D iscontinuation and Missed Dose When discontinuing ONGENTYS, monitor patients and consider adjustment of other dopaminergic therapies as needed. If a dose of ONGENTYS is missed, the next dose should be taken at the scheduled time the next day.

3 DOSAGE FORMS AND STRENGTHS ONGENTYS capsules are available in the following strengths: 50 mg capsules with a dark blue opaque cap and dark pink opaque body; axially printed with “OPC” over “50” in white ink, on both the cap and body. 25 mg capsules with a light blue opaque cap and light pink opaque body; axially printed with “OPC” over “25” in blue ink, on both the cap and body. Capsules: 25 mg and 50 mg. ( 3 )

4 CONTRAINDICATIONS ONGENTYS is contraindicated in patients with: Concomitant use of non-selective monoamine oxidase (MAO) inhibitors [ see Drug Interactions ( 7.1 ) ] . Pheochromocytoma, paraganglioma, or other catecholamine secreting neoplasms. Concomitant use of non-selective monoamine oxidase (MAO) inhibitors. ( 4 ) History of pheochromocytoma, paraganglioma, or other catecholamine secreting neoplasms. ( 4 )

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 )] 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 Amneal Pharmaceuticals at 1-877-835-5472 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 a 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 Parkinson’s 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 a stable dose of levodopa and a DOPA decarboxylase inhibitor, alone or in combination with other PD medications. In Study 1 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 1 and Study 2, a 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 Reactions Adverse 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 2 % in Patients Treated with ONGENTYS and Greater than on Placebo, in Pooled Study 1 and Study 2 Adverse Reactions ONGENTYS 50 mg N=265 % Placebo N=257 % Nervous system disorders Dyskinesia Dizziness 20 3 6 1 Gastrointestinal disorders Constipation Dry mouth 6 3 2 1 Psychiatric disorders Hallucination 1 Insomnia 3 3 1 2 Investigations Blood creatine kinase increased Weight decreased 5 4 2 0 Vascular disorders Hypotension/syncope 2 Hypertension 5 3 1 2 1 Includes hallucinations, hallucinations visual, hallucinations auditory, and hallucinations mixed 2 Includes hypotension, orthostatic hypotension, syncope, and presyncope 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ONGENTYS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Injury, poisoning and procedural complications: Fall Psychiatric disorder : Confusional state

7 DRUG INTERACTIONS 7.1 Non-Selective Monoamine Oxidase (MAO) Inhibitors Both ONGENTYS and non-selective MAO inhibitors (e.g., phenelzine, isocarboxazid, and tranylcypromine) inhibit catecholamine metabolism, leading to increased levels of catecholamines. Concomitant use may increase the risk of possible arrhythmias, increased heart rate, and excessive changes in blood pressure. Concomitant use of ONGENTYS with non-selective MAO inhibitors is contraindicated [see Contraindications ( 4 )] . Selective MAO-B inhibitors can be used concomitantly with ONGENTYS. 7.2 Effect of ONGENTYS on Other Drugs Drugs Metabolized by Catechol-O-Methyltransferase (COMT) Concomitant use of ONGENTYS with drugs metabolized by COMT may affect the pharmacokinetics of those drugs, which may increase the risk of possible arrhythmias, increased heart rate, and excessive changes in blood pressure [see Warnings and Precautions ( 5.1 )] . Drugs known to be metabolized by COMT should be administered with caution. Monitor for changes in heart rate, rhythm, and blood pressure in patients concomitantly treated with ONGENTYS and drugs metabolized by COMT [see Warnings and Precautions ( 5.1 )] .

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 ) 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 Parkinson’s 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. A 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 mother’s 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 1 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 a 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 a 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 …

12.1 Mechanism of Action Opicapone is a 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 a 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).

11 DESCRIPTION ONGENTYS contains opicapone, a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitor. The chemical name of opicapone is 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide with the following structure: The opicapone molecular formula is C15H10Cl2N4O6; and its molecular weight is 413.17. Opicapone is a yellow powder/crystalline solid with limited aqueous solubility. ONGENTYS capsules are intended for oral administration. Each capsule contains 25 mg or 50 mg of opicapone. ONGENTYS also contains the following inactive ingredients: lactose, magnesium stearate, pregelatinized starch, and sodium starch glycolate. The capsule shells contain: FD&C Blue#2, FD&C Red#3, gelatin, and titanium dioxide. ONGENTYS contains opicapone, a peripheral, selective and reversible catechol-O-methyltransferase (COMT) inhibitor. The chemical name of opicapone is 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide with the following structure:

10 OVERDOSAGE No specific antidotes for ONGENTYS are known. As a general measure, removal of ONGENTYS by gastric lavage and/or inactivation by administering activated charcoal should be considered. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an over-exposure occurs, call your poison control center at 1-800-222-1222 or www.poison.org.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ONGENTYS (opicapone) capsules are available as: • 50 mg hard gelatin capsules, Size 1; dark blue opaque cap and dark pink opaque body; axially printed with “OPC” over “50” in white ink, on both the cap and body - Bottle of 30 with child-resistant closure: NDC 64896-403-01 • 25 mg hard gelatin capsules, Size 1; light blue opaque cap and light pink opaque body; axially printed with “OPC” over “25” in blue ink, on both the cap and body - Bottle of 30 with child-resistant closure: NDC 64896-402-01 16.2 Storage and Handling Store at a temperature below 30°C (86°F).

16.1 How Supplied ONGENTYS (opicapone) capsules are available as: • 50 mg hard gelatin capsules, Size 1; dark blue opaque cap and dark pink opaque body; axially printed with “OPC” over “50” in white ink, on both the cap and body - Bottle of 30 with child-resistant closure: NDC 64896-403-01 • 25 mg hard gelatin capsules, Size 1; light blue opaque cap and light pink opaque body; axially printed with “OPC” over “25” in blue ink, on both the cap and body - Bottle of 30 with child-resistant closure: NDC 64896-402-01