hibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena (see clinical pharmacology : clinical studies ).

ts who develop evidence of hepatocellular injury while on tolcapone tablets and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone tablets is reintroduced. accordingly, such patients should not ordinarily be considered for retreatment. in controlled phase 3 trials, increases to more than 3 times the upper limit of normal in alt or ast occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). approximately one third of patients with elevated enzymes had diarrhea. increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. elevations usually occurred within 6 weeks to 6 months of starting treatment. in about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued tolcapone tablets treatment. when treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal. monoamine oxidase (mao) and comt are the two major enzyme systems involved in the metabolism of catecholamines. it is theoretically possible, therefore, that the combination of tolcapone tablets and a non-selective mao inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. for this reason, patients should ordinarily not be treated concomitantly with tolcapone tablets and a non-selective mao inhibitor. tolcapone can be taken concomitantly with a selective mao-b inhibitor (e.g., selegiline). falling asleep during activities of daily living and somnolence tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products [see dosage and administration]. patients taking carbidopa levodopa products alone or with other dopaminergic medications have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes the operation of motor vehicles). some of these episodes resulted in automobile accidents. although many of these patients reported somnolence while on tolcapone tablets, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. some patients reported these events one year after the initiation of treatment. the risk for somnolence was increased with tolcapone tablets treatment (tolcapone tablets 100 mg -18 %, 200 mg-14 %, vs placebo-13 %) compared to placebo treatment. in clinical trials, discontinuation due to somnolence occurred in 1 % of patients treated with 200 mg tolcapone tablets and 0 % of patients treated with 100 mg tolcapone tablets or placebo. falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. for this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with tolcapone tablets. before initiating treatment with tolcapone tablets, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with tolcapone tablets such as the use of concomitant sedating medications and the presence of sleep disorders. consider discontinuing tolcapone tablets in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). if treatment with tolcapone tablets continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if patients become somnolent. there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

develop evidence of hepatocellular injury while on tolcapone tablets and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone tablets is reintroduced. these patients should not ordinarily be considered for retreatment with tolcapone tablets. only prescribe tolcapone tablets for patients taking concomitant carbidopa levodopa therapy. the initial dose of tolcapone tablets is always 100 mg three times per day. the recommended daily dose of tolcapone tablets is also 100 mg tid. in clinical trials, elevations in alt occurred more frequently at the dose of 200 mg tid. while it is unknown whether the risk of acute fulminant liver failure is increased at the 200-mg dose, it would be prudent to use 200 mg only if the anticipated incremental clinical benefit is justified (see boxed warning , warnings , precautions : laboratory tests ). if a patient fails to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), tolcapone tablets should be discontinued. in clinical trials, the first dose of the day of tolcapone tablets was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of tolcapone tablets were given approximately 6 and 12 hours later. in clinical trials, the majority of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesias before beginning treatment. to optimize an individual patient's response, reductions in daily levodopa dose may be necessary. in clinical trials, the average reduction in daily levodopa dose was about 30% in those patients requiring a levodopa dose reduction. (greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.) tolcapone tablets can be combined with both the immediate and sustained release formulations of levodopa/carbidopa. tolcapone tablets may be taken with or without food (see clinical pharmacology ). patients with impaired hepatic function: tolcapone tablets therapy should not be initiated in any patient with liver disease or two sgpt/alt or sgot/ast values greater than the upper limit of normal. (see boxed warning , warnings , and clinical pharmacology ). patients with impaired renal function: no dose adjustment of tolcapone tablets is recommended for patients with mild to moderate renal impairment. however, patients with severe renal impairment should be treated with caution. the safety of tolcapone has not been examined in subjects who had creatinine clearance less than 25 ml/min (see clinical pharmacology ). withdrawing patients from tolcapone tablets: as with any dopaminergic drug, withdrawal or abrupt reduction in the tolcapone tablets dose may lead to emergence of signs and symptoms of parkinson's disease or hyperpyrexia and confusion, a syndrome complex resembling the neuroleptic malignant syndrome (see precautions : events reported with dopaminergic therapy ). if a decision is made to discontinue treatment with tolcapone tablets, then it is recommended to closely monitor the patient and adjust other dopaminergic treatments as needed. this syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. tapering tolcapone tablets has not been systematically evaluated. as the duration of comt inhibition with tolcapone tablets is generally 5 to 6 hours on average, decreasing the frequency of dosage to twice or once a day may not in itself prevent withdrawal effects.

(i.e., not due to viral hepatitis or alcohol) is low. one estimate, based upon transplant registry data, is approximately 3/1,000,000 patients per year in the united states. whether this estimate is an appropriate basis for estimating the increased risk of liver failure among tolcapone tablets users is uncertain. tolcapone tablets users, for example, differ in age and general health status from candidates for liver transplantation. similarly, underreporting of cases may lead to significant underestimation of the increased risk associated with the use of tolcapone tablets. during the premarketing development of tolcapone, two distinct patient populations were studied, patients with end-of-dose wearing-off phenomena and patients with stable responses to levodopa therapy. all patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. adverse reactions are shown for these two populations combined. the most commonly observed adverse reactions in the double-blind, placebo-controlled trials (n=892), with a difference in incidence (tolcapone tablets minus placebo) of at least 5 % or greater in the 100 mg or 200 mg tolcapone tablets- treated groups compared to placebo, were dyskinesia, nausea, diarrhea, anorexia, sleep disorder, vomiting, urine discoloration, somnolence, hallucination, dystonia, and sweating. approximately 16% of the 592 patients who participated in the double-blind, placebo- controlled trials discontinued treatment due to adverse reactions compared to 10% of the 298 patients who received placebo. diarrhea was by far the most frequent cause of discontinuation (approximately 6% in tolcapone patients vs. 1% on placebo). adverse reaction incidence in controlled clinical studies: table 4 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with tolcapone participating in the double-blind, placebo-controlled studies and were numerically more common in at least one of the tolcapone groups. in these studies, either tolcapone or placebo was added to levodopa/carbidopa (or benserazide). the prescriber should be aware that these figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. however, the cited figures do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence rate in the population studied. table 4. summary of patients with adverse reactions after start of trial drug administration(at least 1% in tolcapone tablets group and at least one tolcapone tablets dose group greater than placebo) placebo tolcapone tid n = 298 100 mg n = 296 200 mg n = 298 adverse reactions (%) (%) (%) dyskinesia 20 42 51 nausea 18 30 35 sleep disorder 18 24 25 dystonia 17 19 22 dreaming excessive 17 21 16 anorexia 13 19 23 cramps muscle 17 17 18 orthostatic complaints 14 17 17 somnolence 13 18 14 diarrhea 8 16 18 confusion 9 11 10 dizziness 10 13 6 headache 7 10 11 hallucination 5 8 10 vomiting 4 8 10 constipation 5 6 8 fatigue 6 7 3 upper respiratory tract infection 3 5 7 falling 4 4 6 sweating increased 2 4 7 urinary tract infection 4 5 5 xerostomia 2 5 6 abdominal pain 3 5 6 syncope 3 4 5 urine discoloration 1 2 7 dyspepsia 2 4 3 influenza 2 3 4 dyspnea 2 3 3 balance loss 2 3 2 flatulence 2 2 4 hyperkinesia 1 3 2 chest pain 1 3 1 hypotension 1 2 2 paresthesia 2 3 1 stiffness 1 2 2 arthritis 1 2 1 chest discomfort 1 1 2 hypokinesia 1 1 3 micturition disorder 1 2 1 pain neck 1 2 2 burning 0 2 1 sinus congestion 0 2 1 agitation 0 1 1 bleeding dermal 0 1 1 irritability 0 1 1 mental deficiency 0 1 1 hyperactivity 0 1 1 malaise 0 1 0 panic reaction 0 1 0 tumor skin 0 1 0 cataract 0 1 0 euphoria 0 1 0 fever 0 0 1 alopecia 0 1 0 eye inflamed 0 1 0 hyertonia 0 0 1 tumor uterus 0 1 0 effects of gender on adverse reactions: female patients may be more likely to develop somnolence than males. other adverse events observed during all trials in patients with parkinson's disease: during these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. to provide a meaningful estimate of the proportion of individuals having adverse events, similar types of adverse events were grouped into a smaller number of standardized categories using costart dictionary terminology. these categories are used in the listing below. all reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events and terms too vague to be meaningful are included, without regard to determination of a causal relationship to tolcapone tablets. events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are defined as those occurring in between 1/100 and 1/1000 patients; and rare adverse events are defined as those occurring in fewer than 1/1000 patients. nervous system — frequent: depression, hypesthesia, tremor, speech disorder, vertigo, emotional lability; infrequent: neuralgia, amnesia, extrapyramidal syndrome, hostility, libido increased, manic reaction, nervousness, paranoid reaction, cerebral ischemia, cerebrovascular accident, delusions, libido decreased, neuropathy, apathy, choreoathetosis, myoclonus, psychosis, thinking abnormal, twitching; rare: antisocial reaction, delirium, encephalopathy, hemiplegia, meningitis. digestive system — frequent: tooth disorder; infrequent: dysphagia, gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue disorder, rectal disorder; rare: cholecystitis, duodenal ulcer, gastrointestinal carcinoma, stomach atony. body as a whole — frequent: flank pain, accidental injury, abdominal pain, infection; infrequent: hernia, pain, allergic reaction, cellulitis, infection fungal, viral infection, carcinoma, chills, infection bacterial, neoplasm, abscess, face edema; rare: death. cardiovascular system — frequent: palpitation; infrequent: hypertension, vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia, migraine, aortic stenosis, arrhythmia, arteriospasm, bradycardia, cerebral hemorrhage, coronary artery disorder, heart arrest, myocardial infarct, myocardial ischemia, pulmonary embolus; rare: arteriosclerosis,cardiovascular disorder, pericardial effusion, thrombosis. musculoskeletal system — frequent: myalgia; infrequent: tenosynovitis, arthrosis, joint disorder. urogenital system — frequent: urinary incontinence, impotence; infrequent: prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; rare: bladder calculus, ovarian carcinoma, uterine hemorrhage. respiratory system — frequent: bronchitis, pharyngitis; infrequent: cough increased, rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup; rare: apnea, hypoxia, lung edema. skin and appendages — frequent: rash; infrequent: herpes zoster, pruritus, seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder, furunculosis, herpes simplex urticaria. special senses — frequent: tinnitus; infrequent: diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; rare: glaucoma metabolic and nutritional — infrequent: edema, hypercholesteremia, thirst, dehydration. hemic and lymphatic system — infrequent: anemia; rare: leukemia, thrombocytopenia. endocrine system — infrequent: diabetes mellitus. unclassified — infrequent: surgical procedure.

enylalanine (3-omd) in the brain and periphery. the precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit comt and alter the plasma pharmacokinetics of levodopa. when tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. it is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. tolcapone enters the cns to a minimal extent, but has been shown to inhibit central comt activity in animals. pharmacodynamics comt activity in erythrocytes: studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol- o - methyltransferase (comt) activity after oral administration. the inhibition is closely related to plasma tolcapone concentrations. with a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte comt activity is on average greater than 80%. during multiple dosing with tolcapone (200 mg tid), erythrocyte comt inhibition at trough tolcapone blood concentrations is 30% to 45%. effect on the pharmacokinetics of levodopa and its metabolites: when tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (auc) of levodopa by approximately twofold. this is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). in general, the average peak levodopa plasma concentration (c max ) and the time of its occurrence (t max ) are unaffected. the onset of effect occurs after the first administration and is maintained during long-term treatment. studies in healthy volunteers and parkinson's disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. plasma levels of 3-omd are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa. population pharmacokinetic analyses in patients with parkinson's disease have shown the same effects of tolcapone on levodopa plasma concentrations that occur in healthy volunteers. pharmacokinetics of tolcapone: tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa co-administration. the elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. with tid dosing of 100 mg or 200 mg, c max is approximately 3 mcg/ml and 6 mcg/ml, respectively. absorption: tolcapone is rapidly absorbed, with a t max of approximately 2 hours. the absolute bioavailability following oral administration is about 65%. food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20% (see dosage and administration ). distribution: the steady-state volume of distribution of tolcapone is small (9 l). tolcapone does not distribute widely into tissues due to its high plasma protein binding. the plasma protein binding of tolcapone is >99.9% over the concentration range of 0.32 to 210 mcg/ml. in vitro experiments have shown that tolcapone binds mainly to serum albumin. metabolism and elimination: tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. the main metabolic pathway of tolcapone is glucuronidation; the glucuronide conjugate is inactive. in addition, the compound is methylated by comt to 3- o -methyl-tolcapone. tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. in vitro experiments suggest that the oxidation may be catalyzed by cytochrome p450 3a4 and p450 2a6. the reduction to an amine and subsequent n-acetylation occur to a minor extent. after oral administration of a 14 c-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 l/h. special populations: tolcapone pharmacokinetics are independent of sex, age, body weight, and race (japanese, black and caucasian). polymorphic metabolism is unlikely based on the metabolic pathways involved. hepatic impairment: a study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. in patients with moderate cirrhotic liver disease (child-pugh class b), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. this reduction may increase the average concentration of unbound drug by twofold (see dosage and administration ). tolcapone tablets therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two sgpt/alt or sgot/ast values greater than the upper limit of normal (see boxed warning ). renal impairment: the pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. however, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. the data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 ml/min to 130 ml/min) the pharmacokinetics of tolcapone are unaffected by renal function. this could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. the glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 ml/min (see dosage and administration ). given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected drug interactions: see precautions : drug interactions. clinical studies: the effectiveness of tolcapone tablets as an adjunct to levodopa in the treatment of parkinson's disease was established in three multicenter randomized controlled trials of 13 to 26 weeks' duration, supported by four 6-week trials whose results were consistent with those of the longer trials. in two of the longer trials, tolcapone was evaluated in patients whose parkinson's disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). in the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called non- fluctuators). fluctuating patients: in two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. the formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent "on" (a period of relatively good functioning) and "off" (a period of relatively poor functioning). patients recorded periodically, throughout the duration of the trial, the time spent in each of these states. in addition to the primary outcome, patients were also assessed using sub-parts of the unified parkinson's disease rating scale (updrs), a frequently used multi-item rating scale intended to evaluate mentation (part i), activities of daily living (part ii), motor function (part iii), complications of therapy (part iv), and disease staging (parts v and vi); an investigator's global assessment of change (iga), a subjective scale designed to assess global functioning in 5 areas of parkinson's disease; the sickness impact profile (sip), a multi-item scale in 12 domains designed to assess the patient's functioning in multiple areas; and the change in daily levodopa/carbidopa dose. in one of the studies, 202 patients were randomized in 11 centers in the united states and canada. in this trial, all patients were receiving concomitant levodopa and carbidopa. in the second trial, 177 patients were randomized in 24 centers in europe. in this trial, all patients were receiving concomitant levodopa and benserazide. the following tables display the results of these 2 trials: table 1. us/canadian fluctuator study * compared to placebo. nominal p values are not adjusted for multiple comparisons. ** hours “off” or “on” are based on the percent of waking day “off” or “on”, assuming a 16-hour waking day. primary measure baseline ( hrs ) change from baseline at month 3 ( hrs ) p - value * hours of wake time “ off ” ** placebo 6.2 -1.2 --- 100 mg tid 6.4 -2.0 0.169 200 mg tid 5.9 -3.0 <0.001 hours of wake time “ on ” ** placebo 8.7 1.4 --- 100 mg tid 8.1 2.0 0.267 200 mg tid 9.1 2.9 <0.008 secondary measure baseline change from baseline at month 3 p - value * levodopa total daily dose ( mg ) placebo 948 16 --- 100 mg tid 788 -166 <0.001 200 mg tid 865 -207 <0.001 global ( overall ) % improved placebo --- 42 --- 100 mg tid --- 71 <0.001 200 mg tid --- 91 <0.001 updrs motor placebo 19.5 -0.4 --- 100 mg tid 17.6 -1.9 0.217 200 mg tid 20.6 -2.0 0.210 updrs adl placebo 7.5 -0.3 --- 100 mg tid 7.7 -0.8 0.487 200 mg tid 8.3 0.2 0.412 sip ( total ) placebo 14.7 -2.2 --- 100 mg tid 14.9 -0.4 0.210 200 mg tid 17.6 -0.3 0.216 table 2. european fluctuator study * compared to placebo. nominal p values are not adjusted for multiple comparisons. ** hours “off” or “on” are based on the percent of waking day “off” or “on”, assuming a 16- hour waking day. primary measure baseline ( hrs ) change from baseline at month 3 ( hrs ) p - value * hours of wake time “ off ” ** placebo 6.1 -0.7 --- 100 mg tid 6.5 -2.0 0.008 200 mg tid 6.0 -1.6 0.081 hours of wake time “ on ” ** placebo 8.5 -0.1 --- 100 mg tid 8.1 1.7 0.003 200 mg tid 8.4 1.7 0.003 secondary measure baseline change from baseline at month 3 p - value * levodopa total daily dose ( mg ) placebo 660 -29 --- 100 mg tid 667 -109 0.025 200 mg tid 675 -122 0.010 global ( overall ) % improved placebo --- 37 --- 100 mg tid --- 70 0.003 200 mg tid --- 78 <0.001 updrs motor placebo 24.0 -2.1 --- 100 mg tid 22.4 -4.2 0.163 200 mg tid 22.4 -6.5 0.004 updrs adl placebo 7.9 -0.5 --- 100 mg tid 7.5 -0.9 0.408 200 mg tid 7.7 -1.3 0.097 sip ( total ) placebo 21.6 -0.9 --- 100 mg tid 16.6 -1.9 0.419 200 mg tid 18.4 -4.2 0.011 effects on "off" time and levodopa dose did not differ by age or sex. non-fluctuating patients: in this study, 298 patients with idiopathic parkinson's disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the united states and canada. the primary measure of effectiveness was the activities of daily living portion (subscale ii) of the updrs. in addition, the change in daily levodopa dose, other subscales of the updrs, and the sip were assessed as secondary measures. the results are displayed in the following table table 3. us/canadian non-fluctuator study * compared to placebo. nominal p values are not adjusted for multiple comparisons. primary measure baseline ( hrs ) change from baseline at month 6 p - value * updrs adl placebo 8.5 0.1 --- 100 mg tid 7.5 -1.4 <0.001 200 mg tid 7.9 -1.6 <0.001 secondary measure baseline change from baseline at month 6 p - value * levodopa total daily dose ( mg ) placebo 364 47 --- 100 mg tid 370 -21 <0.001 200 mg tid 381 -32 <0.001 updrs motor placebo 19.7 0.1 --- 100 mg tid 17.3 -2.0 0.018 200 mg tid 16.0 -2.3 0.008 sip ( total ) placebo 6.9 0.4 --- 100 mg tid 7.3 -0.9 0.044 200 mg tid 7.3 -0.7 0.078 percent of patients who developed fluctuations placebo --- 26 --- 100 mg tid --- 19 0.297 200 mg tid --- 14 0.047 effects on activities of daily living did not differ by age or sex.

in association with use of tolcapone tablets. ● there are no laboratory tests that will predict in advance which patients are at an increased risk for liver failure or death from liver failure. ● patients should have the recommended liver blood tests before treatment with tolcapone tablets is begun and periodically for the first 6 months of therapy. after the first six months, periodic liver blood tests should be performed as directed by your physician. if the dose of tolcapone tablets is to be increased, the liver blood tests should be checked before increasing the dose and repeated periodically as described earlier. liver blood tests may help detect if liver failure has occurred but they may do so only after significant damage, that may not go away, has already occurred. ● patients must immediately report any unusual symptoms to their physician and be especially aware of persistent nausea, fatigue, lethargy, decreased appetite, jaundice (yellowing of skin or the whites of the eyes), dark urine, itchiness or right- sided abdominal pain. the above points of information, possibly along with other information, have been explained to me and i have been able to ask my physician questions and discuss risks and benefits associated with tolcapone tablets treatment. patient or patient caregiver signature: ___________________________________________________ date: ________________________________ note to physician : it is strongly recommended that you retain a signed copy of this form with the patient's medical records. supply of patient acknowledgement forms : a supply of patient acknowledgement forms is available, free of charge, from your local ingenus pharmaceuticals representative, or by calling at 1-877-748-1970. permission to use the above patient acknowledgement form by photocopy reproduction is also hereby granted by ingenus pharmaceuticals, llc. u.s.a. rx only manufactured for: ingenus pharmaceuticals, llc orlando, fl 32839-6408 made in india rev: 08/2018