Stalevo

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in the Warnings and Precautions sections of labeling: Falling Asleep During Activities of Daily Living and Somnolence [ see Warnings and Precautions (5.1) ] Hypotension/Orthostatic Hypotension and Syncope [ see Warnings and Precautions (5.2) ] Dyskinesia [ see Warnings and Precautions (5.3) ] Depression and suicidality [ see Warnings and Precautions (5.4) ] Hallucinations/Psychotic-Like Behavior [ see Warnings and Precautions (5.5) ] Impulse Control and/or Compulsive Behaviors [ see Warnings and Precautions (5.6) ] Withdrawal-Emergent Hyperpyrexia and Confusion [ see Warnings and Precautions (5.7) ] Diarrhea and Colitis [ see Warnings and Precautions (5.8) ] Rhabdomyolysis [ see Warnings and Precautions (5.9) ] Peptic Ulcer Disease [ see Warnings and Precautions (5.13) ] The most common adverse reactions (incidence 3% higher than placebo incidence) are dyskinesias, hyperkinesia, diarrhea, nausea, abdominal pain, vomiting, dry mouth and urine discoloration ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 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, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice. Entacapone The most commonly observed adverse reactions (incidence at least 3% greater than placebo incidence) in the double-blind, carbidopa-levodopa-placebo-controlled trials of entacapone (N=1,003 patients) associated with the use of carbidopa-levodopa-entacapone alone and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia, diarrhea, nausea, hyperkinesia, abdominal pain, vomiting, dry mouth, and urine discoloration. The treatment difference incidence for premature study discontinuation for entacapone with levodopa and dopa decarboxylase inhibitor in the double-blind, placebo-controlled trials was 5%. The treatment difference incidence for the most frequent causes of study discontinuation was 2% for diarrhea, and 1% for other specific adverse reactions including psychiatric reasons, dyskinesia/ hyperkinesia, nausea, or abdominal pain. Adverse Reaction Incidence in Controlled Clinical Studies of Entacapone Table 2 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with carbidopa/levodopa and 200 mg of entacapone who participated in the double-blind, placebo-controlled studies, and that were numerically more common in this group than in the carbidopa/levodopa plus placebo group. In these studies, either entacapone or placebo was added to carbidopa/levodopa (or benserazide/levodopa). Table 2: Summary of Patients With Adverse Reactions After Start of Trial Drug Administration At Least 1% in Entacapone Group and Greater Than Placebo SYSTEM ORGAN CLASS Carbidopa/levodopa plus Entacapone Carbidopa/levodopa plus Placebo Adverse Reaction (n=603) % of patients (n=400) % of patients SKIN AND APPENDAGES DISORDERS Sweating Increased 2 1 MUSCULOSKELETAL SYSTEM DISORDERS Back Pain 5 3 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS Dyskinesia 25 15 Hyperkinesia 10 5 Hypokinesia 9 8 Dizziness 8 6 SPECIAL SENSES, OTHER DISORDERS Taste Perversion 1 0 PSYCHIATRIC DISORDERS Anxiety 2 1 Somnolence 2 0 Agitation 1 0 GASTROINTESTINAL SYSTEM DISORDERS Nausea 14 8 Diarrhea 10 4 Abdominal Pain 8 4 Constipation 6 4 Vomiting 4 1 Mouth Dry 3 0 Dyspepsia 2 1 Flatulence 2 0 Gastritis 1 0 Gastrointestinal Disorders NOS 1 0 RESPIRATORY SYSTEM DISORDERS Dyspnea 3 1 PLATELET, BLEEDING AND CLOTTING DISORDERS Purpura 2 1 URINARY SYSTEM DISORDERS Urine Discoloration 10 0 BODY AS A WHOLE-GENERAL DISORDERS Fatigue 6 4 Asthenia 2 1 RESISTANCE MECHANISM DISORDERS Infection Bacterial 1 0 6.2 Postmarketing Experience The following spontaneous reports of adverse events temporally associated with entacapone or Stalevo have been identified since market introduction and are not listed in Table 2. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to entacapone or Stalevo exposure. Hepatitis with mainly cholestatic features has been reported. Effects of Gender and Age on Adverse Reactions No differences were noted in the rate of adverse reactions attributable to entacapone alone by age or gender.

4 CONTRAINDICATIONS Stalevo is contraindicated in patients: Taking nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine). These nonselective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with Stalevo. With narrow-angle glaucoma. Concomitant use of nonselective monoamine oxidase (MAO) inhibitors ( 4 ) Narrow-angle glaucoma ( 4 )

11 DESCRIPTION Stalevo is a combination of carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease. Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C 10 H 14 N 2 O 4 ∙H 2 O, and its structural formula is: Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3. Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C 9 H 11 NO 4 , and its structural formula is: Entacapone, a COMT inhibitor, is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C 14 H 15 N 3 O 5 and its structural formula is: Stalevo is supplied as tablets in 6 strengths: Stalevo 50:12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone Stalevo 75: 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone Stalevo 100: 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone Stalevo125: 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone Stalevo 150: 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone Stalevo 200: 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone Inactive Ingredients: corn starch, croscarmellose sodium, glycerol 85%, hypromellose, magnesium stearate, mannitol, polysorbate 80, povidone, sucrose, red iron oxide, and titanium dioxide. Stalevo 50, Stalevo 100, and Stalevo 150 also contain yellow iron oxide. Chemical Structure Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION Stalevo should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with Stalevo if a decision has been made to add entacapone (see below). Therapy should be individualized and adjusted according to the desired therapeutic response. The optimum daily dosage of Stalevo must be determined by careful titration in each patient ( 2.1 ) Individual tablets should not be split or fractionated. Administer only one tablet at each dosing interval ( 2.6 ) 2.1 Dosing Information The optimum daily dosage of Stalevo must be determined by careful titration in each patient. Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of Stalevo depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (Stalevo 200) than with lower strengths (see Table 1 ). Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting. Table 1: Maximum Recommended Dose of Stalevo in a 24-hour Period Stalevo Dosage Strength Maximum Number of Tablets in a 24-hour Period Stalevo 50, Stalevo 75, Stalevo 100, Stalevo 125, Stalevo 150 8 Stalevo 200 6 2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Stalevo Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of Stalevo containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single Stalevo 100 tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone). 2.3 Converting Patients from Carbidopa and Levodopa Products to Stalevo There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa. Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient's individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of Stalevo. When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of Stalevo at each administration or by decreasing the frequency of administration by extending the time between doses. 2.4 Concomitant Use with Other Anti-Parkinson's Disease Drugs Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) - B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while Stalevo is being administered; however, dosage adjustments of the concomitant medication or Stalevo may be required. 2.5 Decrease or Interruption of Dosing Avoid interruption of Stalevo dosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [ see Warnings and Precautions (5.7) ]. 2.6 Important Administration Instructions Do not split, crush or chew Stalevo tablets. Administer only one tablet at each dosing interval. All strengths of Stalevo contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone. Administer Stalevo with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [ see Clinical Pharmacology (12.3) ] .

1 INDICATIONS AND USAGE Stalevo is indicated for the treatment of Parkinson's disease. Stalevo can be used: To substitute (with equivalent strengths of each of the three components) carbidopa/levodopa and entacapone previously administered as individual products. To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias. Stalevo, a combination drug consisting of levodopa (aromatic amino acid), carbidopa (aromatic amino acid decarboxylation inhibitor), and entacapone (catechol-O-methyltransferase (COMT) inhibitor) is indicated for the treatment of Parkinson's disease. Stalevo is to be used: To substitute (with equivalent strengths of each of the three components) for carbidopa/levodopa and entacapone previously administered as individual products ( 1 ) To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias ( 1 )

10 OVERDOSAGE 10.1 Signs and Symptoms of Overdosage There are very few cases of overdose with levodopa reported in the published literature. Based on the available information, the acute symptoms of levodopa and dopa decarboxylase inhibitor overdose can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdose may give rise to systemic complications, secondary to dopaminergic overstimulation. COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the O-methylation of endogenous and exogenous catechols. In clinical trials, the highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 mcg per mL. The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with carbidopa/levodopa for 14 days in 15 Parkinson's disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 min, compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg entacapone have been administered as 200 mg 10 times daily with carbidopa/levodopa or benserazide/levodopa for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited. 10.2 Management of Overdosage Hospitalization is advised, and general supportive measures should be employed, along with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular, by decreasing its absorption and reabsorption from the GI tract. Intravenous fluids should be administered judiciously and an adequate airway maintained. Respiratory, circulatory and renal function should be monitored and appropriate supportive measures employed. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Hemodialysis or hemoperfusion is unlikely to reduce entacapone levels due to its high binding to plasma proteins. Pyridoxine is not effective in reversing the actions of Stalevo.

7 DRUG INTERACTIONS Drugs metabolized by COMT: use with caution ( 5.11 , 7.2 ) Anti-hypertensive agents: dose adjustment may be required ( 7.3 ) Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa ( 7.4 ) Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of Stalevo ( 7.5 , 7.6 , 7.7 , 7.8 , 7.9 ) Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of Stalevo may be required ( 7.10 ) Drugs metabolized by CYP2C9 (e.g., coumadin): dose adjustment of Stalevo may be required; monitor INR when initiating Stalevo in patients on coumadin ( 7.11 ) 7.1 MAO Inhibitors Patients receiving nonselective MAO inhibitors and carbidopa, levodopa and entacapone may be at risk of increased adrenergic tone. Therefore, the use of Stalevo is contraindicated in patients receiving nonselective MAO inhibitors [ see Contraindications (4) ]. 7.2 Drugs Metabolized by Catechol-O-Methyltransferase (COMT) Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure [ see Warnings and Precautions (5.10) ]. 7.3 Antihypertensive Agents Symptomatic postural hypotension has occurred when carbidopa/levodopa was added to the treatment of patients receiving antihypertensive drugs. When starting therapy with Stalevo, dosage adjustment of antihypertensive drug may be required. 7.4 Tricyclic Antidepressants There have been reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa. 7.5 Dopamine D2 Receptor Antagonists Dopamine D2 receptor antagonists (e.g., metoclopramide, phenothiazines, butyrophenones, risperidone) may reduce the therapeutic effects of levodopa. 7.6 Isoniazid Isoniazid may reduce the therapeutic effects of levodopa, a dose increase may be necessary. 7.7 Phenytoin The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Patients taking phenytoin with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving phenytoin. 7.8 Papaverine The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by papaverine. Patients taking papaverine with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Stalevo dosage should be increased as clinically needed in patients receiving papaverine. 7.9 Iron Salts Iron salts or multi vitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa, carbidopa and entacapone and consequently reduce bioavailability of levodopa, carbidopa and entacapone. 7.10 Drugs Known to Interfere with Biliary Excretion, Glucuronidation, and Intestinal Beta-glucuronidase As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol). 7.11 Drugs Metabolized via CYP2C9 (e.g., coumadin) The dosage of Stalevo should be adjusted as clinically needed in patients using other drugs metabolized via CYP2C9. An interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values on average by 13%. Cases of increased INR in patients concomitantly using warfarin have been reported during the post-approval use of entacapone. Thus, monitoring of INR is recommended when Stalevo treatment is initiated for patients receiving warfarin.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Levodopa Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood-brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease. Carbidopa When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Entacapone Entacapone 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). 12.3 Pharmacokinetics The pharmacokinetics of Stalevo tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo or as carbidopa and levodopa product plus Comtan (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable. Absorption and Distribution Both levodopa and entacapone are rapidly absorbed and eliminated, and their distribution volume is moderately small. Carbidopa is absorbed and eliminated slightly more slowly compared with levodopa and entacapone. There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone, particularly concerning its C max . The food-effect on the Stalevo tablet has not been evaluated. Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa [ see Patient Counseling Information (17) ]. Levodopa The pharmacokinetic properties of levodopa following the administration of single-dose Stalevo (carbidopa, levodopa and entacapone) tablets are summarized in Table 3. Table 3: Pharmacokinetic Characteristics of Levodopa with Different Tablet Strengths of Stalevo (mean ± SD) AUC 0-∞ C max T max Tablet Strength (nanogram∙h per mL) (nanogram per mL) (h) 12.5 mg per 50 mg per 200 mg 1,040 ± 314 470 ± 154 1.1 ± 0.5 25 mg per 100 mg per 200 mg 2,910 ± 715 975 ± 247 1.4 ± 0.6 37.5 mg per 150 mg per 200 mg 3,770 ± 1,120 1,270 ± 329 1.5 ± 0.9 50 mg per 200 mg per 200 mg 6,115 ± 1,536 1,859 ± 455 1.76 ± 0.7 Levodopa is bound to plasma protein only to a minor extent (about 10% to 30%). Carbidopa Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 hours to 3.4 hours on average. The mean C max ranged from about 40 nanogram per mL to 225 nanogram per mL and the mean AUC from 170 nanogram∙h per mL to 1,200 nanogram∙h per mL, with different Stalevo strengths providing 12.5 mg, 25 mg, 37.5 mg, or 50 mg of carbidopa. Carbidopa is approximately 36% bound to plasma protein. Entacapone Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 hour to 1.2 hours on average. The mean C max of entacapone was about 1,200 nanogram per mL to 1,500 nanogram per mL and the AUC 1,250 nanogram∙h per mL to 1,750 nanagram∙h per mL after administration of different Stalevo strengths all providing 200 mg of entacapone. The plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin. Metabolism and Elimination Levodopa The elimination half-life of levodopa, the active moiety of antiparkinsonian activity, was 1.7 hours (range 1.1 hours to 3.2 hours). Levodopa is extensively metabolized to various metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by COMT. Carbidopa The elimination half-life of carbidopa was on average 1.6 hours to 2 hours (range 0.7 hour to 4.0 hours). Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. Entacapone The elimination half-life of entacapone was on average 0.8 hour to 1 hour (0.3 hour to 4.5 hours). Entacapone is almost completely metabolized prior to excretion with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis -isomer, the only active metabolite. Entacapone and the cis -isomer are eliminated in the urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis -isomer glucuronides). The glucuronide conjugate of the cis -isomer is inactive. After oral administration of a 14 C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces. Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly. Renal Impairment Entacapone The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose in subjects with normal, moderate, and severely impaired renal functions, without levodopa and dopa decarboxylase inhibitor coadministration. No significant effects of renal function on the pharmacokinetics of entacapone were found. Levodopa and carbidopa No studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. Hepatic Impairment Entacapone Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher AUC and C max values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Stalevo should be administered with care to patients with biliary obstruction or hepatic disease. Levodopa and carbidopa There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment. Geriatric Use In the pharmacokinetics studies conducted in healthy volunteers following a single dose of carbidopa-, levodopa- and entacapone (as Stalevo or as separate carbidopa/levodopa and Comtan tablets): Levodopa The AUC of levodopa is significantly (on average 10% to 20%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the C max of levodopa between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Carbidopa There is no significant difference in the C max and AUC of carbidopa, between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Entacapone The AUC of entacapone is significantly (on average, 15%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the C max of entacapone between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Gender Pharmacokinetics following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo or as separate carbidopa/levodopa and Comtan tablets in healthy volunteers (age range 45 years to 74 years): Levodopa The plasma exposure (AUC and C max ) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for C max ). These differences are primarily explained by body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight. Carbidopa There is no gender difference in the pharmacokinetics of carbidopa. Entacapone There is no gender difference in the pharmacokinetics of entacapone. Drug Interaction Studies Drug Metabolized by COMT When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration [ see Drug Interactions (7.2) ]. Drugs Metabolized via CYP2C9 Due to its affinity to CYP2C9 in vitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. In an interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values increased on average by 13% [ see Drug Interactions (7.11) ] . 12.6 Hormone Levels Of the ingredients in Stalevo, levodopa is known to depress prolactin secretion and increase growth hormone levels.

12.1 Mechanism of Action Levodopa Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood-brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease. Carbidopa When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Entacapone Entacapone 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).

12.3 Pharmacokinetics The pharmacokinetics of Stalevo tablets has been studied in healthy subjects (age 45 years to 75 years). Overall, following administration of corresponding doses of levodopa, carbidopa and entacapone as Stalevo or as carbidopa and levodopa product plus Comtan (entacapone) tablets, the mean plasma concentrations of levodopa, carbidopa, and entacapone are comparable. Absorption and Distribution Both levodopa and entacapone are rapidly absorbed and eliminated, and their distribution volume is moderately small. Carbidopa is absorbed and eliminated slightly more slowly compared with levodopa and entacapone. There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone, particularly concerning its C max . The food-effect on the Stalevo tablet has not been evaluated. Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients after eating a high protein meal. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa [ see Patient Counseling Information (17) ]. Levodopa The pharmacokinetic properties of levodopa following the administration of single-dose Stalevo (carbidopa, levodopa and entacapone) tablets are summarized in Table 3. Table 3: Pharmacokinetic Characteristics of Levodopa with Different Tablet Strengths of Stalevo (mean ± SD) AUC 0-∞ C max T max Tablet Strength (nanogram∙h per mL) (nanogram per mL) (h) 12.5 mg per 50 mg per 200 mg 1,040 ± 314 470 ± 154 1.1 ± 0.5 25 mg per 100 mg per 200 mg 2,910 ± 715 975 ± 247 1.4 ± 0.6 37.5 mg per 150 mg per 200 mg 3,770 ± 1,120 1,270 ± 329 1.5 ± 0.9 50 mg per 200 mg per 200 mg 6,115 ± 1,536 1,859 ± 455 1.76 ± 0.7 Levodopa is bound to plasma protein only to a minor extent (about 10% to 30%). Carbidopa Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 hours to 3.4 hours on average. The mean C max ranged from about 40 nanogram per mL to 225 nanogram per mL and the mean AUC from 170 nanogram∙h per mL to 1,200 nanogram∙h per mL, with different Stalevo strengths providing 12.5 mg, 25 mg, 37.5 mg, or 50 mg of carbidopa. Carbidopa is approximately 36% bound to plasma protein. Entacapone Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 0.8 hour to 1.2 hours on average. The mean C max of entacapone was about 1,200 nanogram per mL to 1,500 nanogram per mL and the AUC 1,250 nanogram∙h per mL to 1,750 nanagram∙h per mL after administration of different Stalevo strengths all providing 200 mg of entacapone. The plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin. Metabolism and Elimination Levodopa The elimination half-life of levodopa, the active moiety of antiparkinsonian activity, was 1.7 hours (range 1.1 hours to 3.2 hours). Levodopa is extensively metabolized to various metabolites. Two major pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by COMT. Carbidopa The elimination half-life of carbidopa was on average 1.6 hours to 2 hours (range 0.7 hour to 4.0 hours). Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. Entacapone The elimination half-life of entacapone was on average 0.8 hour to 1 hour (0.3 hour to 4.5 hours). Entacapone is almost completely metabolized prior to excretion with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis -isomer, the only active metabolite. Entacapone and the cis -isomer are eliminated in the urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis -isomer glucuronides). The glucuronide conjugate of the cis -isomer is inactive. After oral administration of a 14 C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces. Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly. Renal Impairment Entacapone The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose in subjects with normal, moderate, and severely impaired renal functions, without levodopa and dopa decarboxylase inhibitor coadministration. No significant effects of renal function on the pharmacokinetics of entacapone were found. Levodopa and carbidopa No studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. Hepatic Impairment Entacapone Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher AUC and C max values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Stalevo should be administered with care to patients with biliary obstruction or hepatic disease. Levodopa and carbidopa There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment. Geriatric Use In the pharmacokinetics studies conducted in healthy volunteers following a single dose of carbidopa-, levodopa- and entacapone (as Stalevo or as separate carbidopa/levodopa and Comtan tablets): Levodopa The AUC of levodopa is significantly (on average 10% to 20%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the C max of levodopa between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Carbidopa There is no significant difference in the C max and AUC of carbidopa, between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Entacapone The AUC of entacapone is significantly (on average, 15%) higher in elderly (60 years to 75 years) than younger subjects (45 years to 60 years). There is no significant difference in the C max of entacapone between younger (45 years to 60 years) and elderly subjects (60 years to 75 years). Gender Pharmacokinetics following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo or as separate carbidopa/levodopa and Comtan tablets in healthy volunteers (age range 45 years to 74 years): Levodopa The plasma exposure (AUC and C max ) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for C max ). These differences are primarily explained by body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight. Carbidopa There is no gender difference in the pharmacokinetics of carbidopa. Entacapone There is no gender difference in the pharmacokinetics of entacapone. Drug Interaction Studies Drug Metabolized by COMT When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. Drugs known to be metabolized by COMT should be administered with caution in patients receiving entacapone regardless of the route of administration [ see Drug Interactions (7.2) ]. Drugs Metabolized via CYP2C9 Due to its affinity to CYP2C9 in vitro, entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme. In an interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values increased on average by 13% [ see Drug Interactions (7.11) ] .

20210730

4

3 DOSAGE FORMS AND STRENGTHS Each Stalevo tablet, provided in 6 single-dose strengths, contains carbidopa and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following 6 strengths: Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone. The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side. Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side. Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side. Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side. Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone. The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side. Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone. The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side. Each Stalevo tablet contains a 1:4 ratio of carbidopa to levodopa and 200 mg of entacapone (mg of carbidopa per mg of levodopa per mg of entacapone) Stalevo 50 (12.5 mg per 50 mg per 200 mg) Stalevo 75 (18.75 mg per 75 mg per 200 mg) Stalevo 100 (25 mg per 100 mg per 200 mg) Stalevo 125 (31.25 mg per 125 mg per 200 mg) Stalevo 150 (37.5 mg per 150 mg per 200 mg) Stalevo 200 (50 mg per 200 mg per 200 mg)

Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide ferric oxide yellow brownish or greyish-red round, biconvex LCE;50 Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide light brownish red LCE;75 Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide ferric oxide yellow brownish or greyish-red LCE;100 Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide light brownish red LCE;125 Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide ferric oxide yellow brownish or greyish-red elongated-ellipse shaped LCE;150 Stalevo carbidopa, levodopa, and entacapone carbidopa carbidopa anhydrous levodopa levodopa entacapone entacapone starch, corn croscarmellose sodium glycerin hypromellose, unspecified magnesium stearate mannitol polysorbate 80 povidone, unspecified sucrose ferric oxide red titanium dioxide dark brownish red LCE;200

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In rats, oral administration of carbidopa-levodopa for 2 years resulted in no evidence of carcinogenicity at doses of approximately 2 times (carbidopa)-4 times (levodopa) the maximum recommended human dose (MRHD). Two-year carcinogenicity studies of entacapone were conducted in mice and rats. In mice, no increase in tumors was observed at oral doses of 100, 200 and 400 mg/kg/day. At the highest dose tested, plasma exposures (AUC) were 4 times higher than that in humans at the maximum recommended daily dose (MRDD) of 1,600 mg. In rats administered oral doses of 20, 90, or 400 mg/kg/day, an increased incidence of renal tubular adenomas and carcinomas was observed in males at the highest dose tested. Plasma AUCs at the higher dose not associated with increased renal tumors (90 mg/kg/day) were approximately 5 times that in humans at the MRDD of entacapone. The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not been evaluated. Mutagenesis Carbidopa was mutagenic in the in vitro bacterial reverse mutation (Ames) assay in the presence and absence of metabolic activation, and in the in vitro mouse lymphoma thymidine kinase ( tk) assay in the absence of metabolic activation. Carbidopa was negative in the in vivo mouse micronucleus assay. Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with carbidopa-levodopa, was negative in the in vivo mouse micronucleus and in the Ames assays. Impairment of Fertility In reproduction studies, no effects on fertility were found in rats receiving carbidopa-levodopa at doses of approximately 2 times (carbidopa)-4 times (levodopa) the MRHD. In rats treated orally with entacapone (up to 700 mg/kg/day), no effects on fertility or general reproductive performance were observed. Plasma exposures (AUC) at the highest dose tested were approximately 30 times that in humans at the MRHD of entacapone. Delayed mating was evident in females at the highest dose tested.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In rats, oral administration of carbidopa-levodopa for 2 years resulted in no evidence of carcinogenicity at doses of approximately 2 times (carbidopa)-4 times (levodopa) the maximum recommended human dose (MRHD). Two-year carcinogenicity studies of entacapone were conducted in mice and rats. In mice, no increase in tumors was observed at oral doses of 100, 200 and 400 mg/kg/day. At the highest dose tested, plasma exposures (AUC) were 4 times higher than that in humans at the maximum recommended daily dose (MRDD) of 1,600 mg. In rats administered oral doses of 20, 90, or 400 mg/kg/day, an increased incidence of renal tubular adenomas and carcinomas was observed in males at the highest dose tested. Plasma AUCs at the higher dose not associated with increased renal tumors (90 mg/kg/day) were approximately 5 times that in humans at the MRDD of entacapone. The carcinogenic potential of entacapone administered in combination with carbidopa-levodopa has not been evaluated. Mutagenesis Carbidopa was mutagenic in the in vitro bacterial reverse mutation (Ames) assay in the presence and absence of metabolic activation, and in the in vitro mouse lymphoma thymidine kinase ( tk) assay in the absence of metabolic activation. Carbidopa was negative in the in vivo mouse micronucleus assay. Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with carbidopa-levodopa, was negative in the in vivo mouse micronucleus and in the Ames assays. Impairment of Fertility In reproduction studies, no effects on fertility were found in rats receiving carbidopa-levodopa at doses of approximately 2 times (carbidopa)-4 times (levodopa) the MRHD. In rats treated orally with entacapone (up to 700 mg/kg/day), no effects on fertility or general reproductive performance were observed. Plasma exposures (AUC) at the highest dose tested were approximately 30 times that in humans at the MRHD of entacapone. Delayed mating was evident in females at the highest dose tested.

NDA021485

Stalevo

carbidopa, levodopa, and entacapone

52427-809

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label - 805 NDC 52427-805-01 Stalevo ® 50 carbidopa USP 12.5 mg levodopa USP 50 mg and entacapone 200 mg Rx only 100 Tablets Do not combine tablets to achieve a higher strength tablet due to the risk of entacapone overdose. 50 mg - 100 Tablet Bottle Label

Manufactured by: Orion Corporation Orion Pharma, Orionintie 1 FI-02200 Espoo, Finland Distributed by: Almatica Pharma LLC Morristown, NJ 07960 USA Rev. 05/2020 PI805-00

17 PATIENT COUNSELING INFORMATION Falling Asleep During Activities of Daily Living and Somnolence Advise patients about the potential for sedating effects associated with Stalevo including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should not drive a motor vehicle, operate heavy machinery or engage in other potentially dangerous activities until they have gained sufficient experience with Stalevo to determine whether or not it affects their mental and/or motor performance adversely [ see Warnings and Precautions (5.1) ]. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Advise patients to speak with their health care prescriber before taking alcohol, sedating medications, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) because of the possible additive effects in combination with Stalevo. Hypotension, Orthostatic Hypotension and Syncope Advise patients that they may develop symptomatic (or asymptomatic) postural (orthostatic) hypotension or non-orthostatic hypotension while taking Stalevo. Hypotension/orthostatic hypotension may occur more frequently during initial therapy. Patients should not rise rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with Stalevo. Advise patients about the potential for syncope in patients using dopamine agonists. For this reason, inform patients about the possibility of syncope while taking Stalevo [ see Warnings and Precautions (5.2) ]. Dyskinesias Inform patients that Stalevo may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.3) ]. Hallucinations and/or Psychotic-Like Behavior Inform patients that hallucinations and other psychotic-like behavior can occur while taking Stalevo [ see Warnings and Precautions (5.5) ]. Impulse Control and/or Compulsive Behaviors Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications used for the treatment of Parkinson's disease, including Stalevo. Ask patients about the development of new or increased gambling urges, sexual urges, urges for uncontrolled spending, or other intense urges while being treated with Stalevo. Advise patients to inform their physician or health care provider if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Stalevo. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Stalevo [ see Warnings and Precautions (5.6) ]. Withdrawal-Emergent Hyperpyrexia and Confusion Advise patients that they may develop fever and confusion as part of a syndrome resembling NMS and possibly with other clinical features (e.g., muscle rigidity, autonomic dysfunction, hyper- or hypotension, etc.). This fever and confusion syndrome may particularly occur with dose reductions or withdrawal of Stalevo but may also develop after initiation of treatment. Advise patients to contact their healthcare provider if they wish to discontinue or decrease the dose of Stalevo and to contact a health care provider if they develop fever and confusion [ see Warnings and Precautions (5.7) ]. Diarrhea and Colitis Inform the patients that diarrhea may occur with Stalevo and it may have a delayed onset. Sometimes prolonged diarrhea may be caused by colitis (inflammation of the large intestine). Patients with diarrhea should drink fluids to maintain adequate hydration and monitor for weight loss. If diarrhea associated with Stalevo is prolonged, discontinuing the drug is expected to lead to resolution. If diarrhea continues after stopping Stalevo, further diagnostic investigations may be needed. In some cases, diarrhea may be associated with colitis [ see Warnings and Precautions (5.8) ]. Rhabdomyolysis Advise patients that they may develop rhabdomyolysis and myalgia if they experience prolonged motor activity including dyskinesia. This event may also be associated with fever and confusion [ see Warnings and Precautions (5.9) ]. Nausea and Vomiting Inform patients that Stalevo may cause nausea and vomiting may occur more frequently during initial therapy and may require dose adjustment. Instructions for Use Instruct patients to take Stalevo only as prescribed. Instruct patients to only take a single tablet of Stalevo at each dosing interval. Instruct patients not to take multiple tablets or additional portions of tablets to achieve a higher dose of levodopa. Advise patients not to split, crush, or chew Stalevo. Inform the patient that Stalevo is a formulation of carbidopa/levodopa combined with entacapone that is designed to begin release of ingredients within 30 minutes after ingestion. It is important that Stalevo be taken at regular intervals according to the schedule outlined by the physician. Caution the patient not to change the prescribed dosage regimen and not to add any additional antiparkinsonian medications, including other carbidopa/levodopa preparations, without first consulting the physician. Advise patients that "off" episodes ("wearing-off" of drug effect) occur at the end of the dosing interval but unpredictable "off" episodes may occur at any time. Advise the patient to notify a health care provider for possible treatment adjustments if such response poses a problem to the patient's everyday life. Advise patients that dark coloration (red, brown, or black) may appear in saliva, urine, or sweat after taking Stalevo. Although the color appears to be clinically insignificant, garments may become discolored. Advise patients that a change in diet to foods that are high in protein may delay the absorption of levodopa. Excessive acidity also delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multi-vitamin tablets) may also reduce the effectiveness of Stalevo. Pregnancy Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy [ see Use in Specific Populations (8.1) ]. Lactation Instruct patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant [ see Use in Specific Populations (8.2) ].

14 CLINICAL STUDIES The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson's disease was established in three 24-week multicenter, randomized, double-blind, placebo-controlled studies in patients with Parkinson's disease. In 2 of these studies (Studies 1 and 2), the patients' disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of these studies, patients were stabilized on levodopa for 2 weeks to 4 weeks. There is limited experience using entacapone in patients who do not experience fluctuations. In Studies 1 and 2, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of carbidopa/levodopa (up to 10 times daily, but patients averaged 4 doses to 6 doses per day). The double-blind portion of both studies was 6 months long. Patients periodically recorded the time spent in the "On" and "Off" states in home diaries throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18 hour diary recorded day (6 a.m. to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state. In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator's and patient's global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson's disease; and the change in daily carbidopa/levodopa dose. In Study 1, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Study 1), all of whom received concomitant levodopa plus dopa decarboxylase inhibitor (either carbidopa/levodopa or benserazide/levodopa). In Study 2, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant carbidopa/levodopa. The following tables (Table 4 and Table 5) display the results of these two studies: Table 4: Efficacy Results of Study 1 Primary Measure from Home Diary (from an 18-hour Diary Day) Baseline Change from Baseline at Month 6 Mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure. p-value vs. placebo Hours of Awake Time "On" Placebo 9.2 +0.1 – Entacapone 9.3 +1.5 less than 0.001 Duration of "On" Time After First AM Dose (Hrs) Placebo 2.2 0.0 – Entacapone 2.1 +0.2 less than 0.05 Secondary Measures from Home Diary (from an 18-hour Diary Day) P values for Secondary Measures are nominal P values without any adjustment for multiplicity. Hours of Awake Time "Off" Placebo 5.3 0.0 – Entacapone 5.5 -1.3 less than 0.001 Proportion of Awake Time "On" Not an endpoint for this study but primary endpoint in the North American Study. (%) Placebo 63.8 +0.6 – Entacapone 62.7 +9.3 less than 0.001 Levodopa Total Daily Dose (mg) Placebo 705 +14 – Entacapone 701 -87 less than 0.001 Frequency of Levodopa Daily Intakes Placebo 6.1 +0.1 – Entacapone 6.2 - 0.4 less than 0.001 Other Secondary Measures Baseline Change from Baseline at Month 6 p-value vs. placebo Investigator's Global (overall) % Improved At least one category change at endpoint. Placebo – 28 – Entacapone – 56 less than 0.01 Patient's Global (overall) % Improved § Placebo – 22 – Entacapone – 39 N.S. Not significant. UPDRS Total Placebo 37.4 -1.1 – Entacapone 38.5 -4.8 less than 0.01 UPDRS Motor Placebo 24.6 -0.7 – Entacapone 25.5 -3.3 less than 0.05 UPDRS ADL Placebo 11.0 -0.4 – Entacapone 11.2 -1.8 less than 0.05 Table 5: Efficacy Results of Study 2 Primary Measure from Home Diary (for a 24-hour Diary Day) Baseline Change from Baseline at Month 6 Mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure. p-value vs. placebo Percent of Awake Time "On" Placebo 60.8 +2.0 – Entacapone 60.0 +6.7 less than 0.05 Secondary Measures from Home Diary (for a 24-hour Diary Day) P values for Secondary Measures are nominal P values without any adjustment for multiplicity. Hours of Awake Time "Off" Placebo 6.6 -0.3 – Entacapone 6.8 -1.2 less than 0.01 Hours of Awake Time "On" Placebo 10.3 +0.4 – Entacapone 10.2 +1.0 N.S. Not significant. Levodopa Total Daily Dose (mg) Placebo 758 +19 – Entacapone 804 -93 less than 0.001 Frequency of Levodopa Daily Intakes Placebo 6.0 +0.2 – Entacapone 6.2 0.0 N.S. ‡ Other Secondary Measures † Baseline Change from Baseline at Month 6 p-value vs. placebo Investigator's Global (overall) % Improved At least one category change at endpoint. Placebo – 21 – Entacapone – 34 less than 0.05 Patient's Global (overall) % Improved § Placebo – 20 – Entacapone – 31 less than 0.05 UPDRS Total Score change at endpoint similarly to the Nordic Study. Placebo 35.6 +2.8 – Entacapone 35.1 -0.6 less than 0.05 UPDRS Motor ¶ Placebo 22.6 +1.2 – Entacapone 22.0 -0.9 less than 0.05 UPDRS ADL ¶ Placebo 11.7 +1.1 – Entacapone 11.9 0.0 less than 0.05 Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline. Withdrawal of entacapone: In Study 2, abrupt withdrawal of entacapone, without alteration of the dose of carbidopa/levodopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within 2 weeks following levodopa dose increase on average by 80 mg. In Study 1, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed 2 weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg. In the third placebo-controlled trial (Study 3), a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other 2 studies, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily "On" time were the primary measures of effectiveness. Results for the primary measures, as well as for some secondary measures are presented in Table 6. Table 6: Efficacy Results of Study 3 Primary Measures Baseline Change from Baseline at Month 6 p-value vs. placebo (LOCF) UPDRS ADL Total population; score change at endpoint. Placebo 12.0 +0.5 – Entacapone 12.4 -0.4 less than 0.05 UPDRS Motor* Placebo 24.1 +0.1 – Entacapone 24.9 -2.5 less than 0.05 Hours of Awake Time "On" (Home Diary) Fluctuating population, with 5 doses to 10 doses; score change at endpoint. Placebo 10.1 +0.5 – Entacapone 10.2 +1.1 N.S. Not significant. Secondary Measures P values for Secondary Measures are nominal P values without any adjustment for multiplicity. Baseline Change from Baseline at Month 6 p-value vs. placebo UPDRS Total * Placebo 37.7 +0.6 – Entacapone 39.0 -3.4 less than 0.05 Percent of Awake Time "On" (Home Diary) ** Placebo 59.8 +3.5 – Entacapone 62.0 +6.5 N.S. ‡ Hours of Awake Time "Off" (Home Diary) Placebo 6.8 -0.6 – Entacapone 6.3 -1.2 0.07 Levodopa Total Daily Dose (mg)* Placebo 572 +4 – Entacapone 566 -35 N.S. Frequency of Levodopa Daily Intake* Placebo 5.6 +0.2 – Entacapone 5.4 0.0 less than 0.01 Global (overall) % Improved Total population; at least one category change at endpoint. Placebo – 34 – Entacapone – 38 N.S. ‡

8.5 Geriatric Use Of the total number of subjects in clinical studies of Stalevo, 43.8% were 65 years old and over, while 7.2% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be excluded. Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years [ see Clinical Pharmacology (12.3) ].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of Stalevo in pregnant women. In animals, administration of carbidopa-levodopa or entacapone during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations ( see Data ). The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal data In nonclinical studies in which carbidopa-levodopa was administered to pregnant animals, increased incidences of visceral and skeletal malformations were observed in rabbits at all doses and ratios of carbidopa-levodopa tested, which ranged from 10 times (carbidopa)-5 times (levodopa) to 20 times (carbidopa)-10 times (levodopa) the maximum recommended human dose (MRHD) of 1,600 mg/day. In rats, there was a decrease in the number of live pups delivered by dams receiving approximately two times (carbidopa)-five times (levodopa) the MRHD throughout organogenesis. No effects on malformation frequencies were observed in mice receiving up to 20 times the MRHD of carbidopa-levodopa. In embryo-fetal development studies of entacapone, pregnant animals received doses of up to 1,000 mg/kg/day (rats) or 300 mg/kg/day (rabbits) throughout organogenesis. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma entacapone exposure (AUC) associated with this dose was approximately 34 times that in humans at the MRHD. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternally toxic doses of 100 mg/kg/day (plasma AUCs less than that in humans at the MRHD) or greater. There were no increases in malformation rates in these studies. When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg/kg/day (plasma AUCs seven times that in humans at the MRHD) or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day (plasma AUCs 28 times that in humans at the MRHD) to rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairment in the offspring.

8 USE IN SPECIFIC POPULATIONS Pregnancy: based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of Stalevo in pregnant women. In animals, administration of carbidopa-levodopa or entacapone during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations ( see Data ). The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal data In nonclinical studies in which carbidopa-levodopa was administered to pregnant animals, increased incidences of visceral and skeletal malformations were observed in rabbits at all doses and ratios of carbidopa-levodopa tested, which ranged from 10 times (carbidopa)-5 times (levodopa) to 20 times (carbidopa)-10 times (levodopa) the maximum recommended human dose (MRHD) of 1,600 mg/day. In rats, there was a decrease in the number of live pups delivered by dams receiving approximately two times (carbidopa)-five times (levodopa) the MRHD throughout organogenesis. No effects on malformation frequencies were observed in mice receiving up to 20 times the MRHD of carbidopa-levodopa. In embryo-fetal development studies of entacapone, pregnant animals received doses of up to 1,000 mg/kg/day (rats) or 300 mg/kg/day (rabbits) throughout organogenesis. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma entacapone exposure (AUC) associated with this dose was approximately 34 times that in humans at the MRHD. Increased frequencies of abortions and late/total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternally toxic doses of 100 mg/kg/day (plasma AUCs less than that in humans at the MRHD) or greater. There were no increases in malformation rates in these studies. When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg/kg/day (plasma AUCs seven times that in humans at the MRHD) or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day (plasma AUCs 28 times that in humans at the MRHD) to rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairment in the offspring. 8.2 Lactation Risk Summary Levodopa has been detected in human milk after administration of carbidopa-levodopa. There are no data on the presence of entacapone or carbidopa in human milk, the effects of levodopa, carbidopa, or entacapone on the breastfed infant, or the effects on milk production. However, inhibition of lactation may occur because levodopa decreases secretion of prolactin [ see Clinical Pharmacology (12.6) ]. Carbidopa and entacapone are excreted in rat milk. In lactating rat, oral administration of radiolabeled entacapone resulted in levels of entacapone and/or metabolites in milk up to 2 to 3 times that in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Stalevo and any potential adverse effects on the breastfed infant from Stalevo or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Stalevo, 43.8% were 65 years old and over, while 7.2% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be excluded. Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years [ see Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment Renal impairment does not affect pharmacokinetics of entacapone. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment [ see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment or Biliary Obstruction There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment. Stalevo should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone [ see Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Stalevo (carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following six strengths: Stalevo 50 film-coated tablets containing 12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone. The round, bi-convex shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 50" on one side. HDPE bottle of 100 tablets NDC 52427‑805‑01 Stalevo 75 film-coated tablets containing 18.75 mg of carbidopa, 75 mg of levodopa, and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 75" on one side. HDPE bottle of 100 tablets NDC 52427‑809‑01 Stalevo 100 film-coated tablets containing 25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone. The oval-shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 100" on one side. HDPE bottle of 100 tablets NDC 52427‑816‑01 Stalevo 125 film-coated tablets containing 31.25 mg of carbidopa, 125 mg of levodopa, and 200 mg of entacapone. The oval-shaped tablets are light brownish red, unscored and embossed with code "LCE 125" on one side. HDPE bottle of 100 tablets NDC 52427‑827‑01 Stalevo 150 film-coated tablets containing 37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone. The elongated-ellipse shaped tablets are brownish- or greyish-red, unscored, and embossed "LCE 150" on one side. HDPE bottle of 100 tablets NDC 52427‑834‑01 Stalevo 200 film-coated tablets containing 50 mg of carbidopa, 200 mg of levodopa, and 200 mg of entacapone. The oval shaped tablets are dark brownish red, unscored, and embossed "LCE 200" on one side. HDPE bottle of 100 tablets NDC 52427‑842‑01 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Dispense in tight container (USP).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Dispense in tight container (USP).