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Tolcapone
Overview
What is Tolcapone?
Tolcapone tablets USP contains 100 mg of tolcapone.
Tolcapone, an inhibitor of catechol--methyltransferase (COMT), is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. It is a yellow, odorless, non-hygroscopic, fine powder with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Its empirical formula is CHNO and its structural formula is:
Inactive ingredients: Core: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate, talc and magnesium stearate. Film coating: iron oxide yellow, iron oxide red, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.
What does Tolcapone look like?
What are the available doses of Tolcapone?
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What should I talk to my health care provider before I take Tolcapone?
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How should I use Tolcapone?
Tolcapone tablets USP are indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone tablets USP should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because tolcapone tablets USP, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from tolcapone tablets USP.
The effectiveness of tolcapone tablets USP was demonstrated in randomized controlled trials in patients receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor whoexperienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena (see CLINICAL PHARMACOLOGY:
Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections).
Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: ).
Laboratory Tests
Withdrawing Patients From Tolcapone:
Events Reported With Dopaminergic Therapy
What interacts with Tolcapone?
Tolcapone tablets are contraindicated in patients with liver disease, inpatients who were withdrawn from tolcapone because of evidence of tolcapone–induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.
Tolcapone is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication (see PRECAUTIONS:
What are the warnings of Tolcapone?
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against colitis.
Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS:
Patients who develop evidence of hepatocellular injury while on tolcapone and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone 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 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
Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
Falling Asleep During Activities of Daily Living and Somnolence
Tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products . 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, 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 treatment (Tolcapone 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 and 0 % of patients treated with 100 mg tolcapone 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.
Before initiating treatment with tolcapone, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with tolcapone such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing tolcapone 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 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.
What are the precautions of Tolcapone?
Hypotension/Syncope:
In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension.
In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg tolcapone tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg tolcapone tid, respectively, withdrawing from the trials prematurely. Discontinuing tolcapone for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of tolcapone, it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg tolcapone tid groups.
Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite).
No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown.
It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).
In clinical trials, hallucinations developed in approximately 5% of patients treated with placebo, compared to 8% and 10% of patients treated with 100 mg or 200 mg three times per day, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3% of patients treated with placebo, compared to 1.4% and 1.0% of patients treated with tolcapone 100 mg or 200 mg tolcapone three times per day, respectively. Hallucinations led to hospitalization in 0.0% of patients in the placebo group, compared to 1.7% and 0.0% of patients treated with 100 mg or 200 mg tolcapone three times per day, respectively.
In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming.The incidence of hallucination may be increased in elderly patients over 75 years treated with tolcapone .
Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during tolcapone treatment or after starting or increasing the dose of tolcapone. Other drugs prescribed to improve the symptoms of Parkinson’s disease may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with tolcapone because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of tolcapone.
Tolcapone may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. Dyskinesia was the most common adverse reaction observed in controlled trials and developed in approximately 20% of patients treated with placebo, compared to 42% and 51% of patients treated with tolcapone 100 mg or 200 mg three times daily, respectively. The rates of withdrawal for dyskinesia were 0.0% in the placebo group, compared to 0.3% and 1.0% in the groups receiving tolcapone 100 mg or 200 mg three times a day, respectively.
Reports suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. These reports are associated with patients taking tolcapone in conjunction with carbidopa/levodopa, as well as other medications that increase central dopaminergic tone and that are used to treat patients with Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with tolcapone. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking tolcapone
Cases of severe rhabdomyolysis, with one case of multi-organ system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, tolcapone played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in and (see PRECAUTIONS: ).
No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution (see CLINICAL PHARMACOLOGY: and DOSAGE AND ADMINISTRATION).
When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments that would confirm the theory have not been conducted.
Because of the risk of liver injury, tolcapone therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction.
The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg tolcapone tid, respectively. The etiology of the increase with tolcapone has not always been explained (for example, by urinary tract infection or warfarin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg tolcapone tid, respectively.
The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone.
In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. It is difficult to determine if tolcapone played a role in the pathogenesis of these events because these patients received several concomitant medications affecting the central nervous system such as monoaminergic (i.e., MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic agents.
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., tolcapone) that increase dopaminergic activity can cause them is unknown.
Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using tolcapone for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
INFORMATION FOR PATIENTS
Patients should be instructed to take tolcapone only as prescribed.
Tolcapone should not be used by patients until there has been a complete discussion of the risks and the patient has provided written acknowledgement that the risks have been explained (see PATIENT ACKNOWLEDGEMENT OF RISKS section).
Inform patients about clinical signs and symptoms that suggest the onset of hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness) (see WARNINGS). If symptoms of hepatic failure occur, patients should be advised to contact their physician immediately.
Inform patients of the need to have regular blood tests to monitor liver enzymes.
Advise patients that sleepiness or drowsiness may occur and that they should not drive a car or operate other complex machinery until they have gained sufficient experience on tolcapone to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients to exercise caution while driving, operating machines, or working at heights during treatment with tolcapone. Because of the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with tolcapone. Inform patients that nausea may occur, especially at the initiation of treatment with tolcapone.
Inform patients that hallucinations and other psychotic-like behavior may occur.
Advise patients about the possibility of developing or worsening of existing dyskinesia and/or dystonia after starting tolcapone.
Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Advise patients to rise slowly, especially after long periods of sitting or lying down. Hypotension may be more likely when patients first start treatment with tolcapone.
Instruct patients and caregivers to report intense urges to gamble, increased sexual urges, increase in spending money, binge eating, and other intense urges as well as the inability to control these urges to the prescriber while taking tolcapone.
Although tolcapone has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS: ).
Tolcapone is excreted into maternal milk in rats. Because of the possibility that tolcapone may be excreted into human milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
LABORATORY TESTS
Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, it is not clear that periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure. However, it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Accordingly, the following liver monitoring program is recommended.
Discontinue tolcapone if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (e.g., persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).
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Rhabdomyolysis
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DRUG INTERACTIONS
Protein Binding:
Drugs Metabolized by Catechol-O-Methyltransferase (COMT):
Effect of Tolcapone on the Metabolism of Other Drugs:
Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are co-administered.
Drugs That Increase Catecholamines:
When tolcapone was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson’s disease patients being treated with tolcapone and levodopa/carbidopa.
In clinical trials, patients receiving tolcapone/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
Carcinogenesis:
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PREGNANCY
Pregnancy Category C:
Tolcapone, when administered alone during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 times and 15 times the recommended daily clinical dose of 600 mg, on a mg/ mbasis, respectively). In rabbits, however, an increased rate of abortion occurred at a dose of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m basis) or greater. Evidence of maternal toxicity (decreased weight gain, death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When tolcapone was administered to female rats during the last part of gestation and throughout lactation, decreased litter size and impaired growth and learning performance in female pups were observed at a dose of 250/150 mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation due to high rate of maternal mortality; equivalent to 4.8/2.9 times the clinical dose on a mg/m basis).
Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20 mg/kg/day) produced an increased incidence of fetal malformations (primarily external and skeletal digit defects) compared to levodopa/carbidopa alone when pregnant rabbits were treated throughout organogenesis. Plasma exposures to tolcapone (based on AUC) were 0.5 times the expected human exposure, and plasma exposures to levodopa were 6 times higher than those in humans under therapeutic conditions. In a combination embryo-fetal development study in rats, fetal body weights were reduced by the combination of tolcapone (10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected human exposure or greater: levodopa exposures were 21 times the expected human exposure or greater. The high dose of 50 mg/kg/day of tolcapone given alone was not associated with reduced fetal body weight (plasma exposures of 1.4 times the expected human exposure).
There is no experience from clinical studies regarding the use of tolcapone in pregnant women. Therefore, tolcapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING WOMEN
In animal studies, tolcapone was excreted into maternal rat milk.
It is not known whether tolcapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tolcapone is administered to a nursing woman
PEDIATRIC USE
There is no identified potential use of tolcapone in pediatric patients.
GERIATRIC USE
Parkinson’s disease is primarily an affliction of the elderly. Consequently, the mean age of patients in tolcapone clinical trials was 60 to 65 years. To investigate safety as it relates to advancing age, three subgroups were identified: less than 65 years, 65 to 75 years, and greater than 75 years. There were generally no consistent age-related trends in safety parameters. However, patients greater than 75 years of age may be more likely to develop hallucinations than patients less than 75 years of age, while patients over 75 may be less likely to develop dystonia (see PRECAUTIONS: ). In tolcapone clinical trials, measures of therapeutic efficacy (effects on “Off” time, levodopa dose, and effects on Activities of Daily Living) were not affected by age (see CLINICAL PHARMACOLOGY: ). Tolcapone pharmacokinetics have not been found to be affected by age (see CLINICAL PHARMACOLOGY: ).
What are the side effects of Tolcapone?
ADVERSE REACTIONS: Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. All 3 cases were reported within the first six months of initiation of treatment with tolcapone. Analysis of the laboratory monitoring data in over 3,400 tolcapone-treated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with tolcapone.
Effects of Gender on Adverse Reactions:
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.
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.
depression, hypesthesia, tremor, speech disorder, vertigo, emotional lability; 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; : antisocial reaction, delirium, encephalopathy, hemiplegia, meningitis.
— tooth disorder; dysphagia, gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue disorder, rectal disorder; : cholecystitis, duodenal ulcer, gastrointestinal carcinoma, stomach atony.
— flank pain, accidental injury, abdominal pain, infection; hernia, pain, allergic reaction, cellulitis, infection fungal, viral infection, carcinoma, chills, infection bacterial, neoplasm, abscess, face edema; death.
— palpitation; : 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; arteriosclerosis, cardiovascular disorder, pericardial effusion, thrombosis.
— myalgia; tenosynovitis, arthrosis, joint disorder.
urinary incontinence, impotence; prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; bladder calculus, ovarian carcinoma, uterine hemorrhage.
bronchitis, pharyngitis; cough increased, rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup; apnea, hypoxia, lung edema.
— rash; herpes zoster, pruritus, seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder, furunculosis, herpes simplex, urticaria.
tinnitus; diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; glaucoma.
edema, hypercholesteremia, thirst, dehydration.
anemia; leukemia, thrombocytopenia.
diabetes mellitus.
surgical procedure.
| Placebo | Tolcapone tid | |||
|---|---|---|---|---|
| 100 mg | 200 mg | |||
| N = 298 | N = 296 | 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 | |
| Hypertonia | 0 | 0 | 1 | |
| Tumor Uterus | 0 | 1 | 0 |
What should I look out for while using Tolcapone?
Tolcapone tablets are contraindicated in patients with liver disease, inpatients who were withdrawn from tolcapone because of evidence of tolcapone–induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.
Tolcapone is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication (see PRECAUTIONS:
(SEE BOXED WARNING) Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections)
Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS:
Patients who develop evidence of hepatocellular injury while on tolcapone and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone 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 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
Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
Falling Asleep During Activities of Daily Living and Somnolence
Tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products . 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, 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 treatment (Tolcapone 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 and 0 % of patients treated with 100 mg tolcapone 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.
Before initiating treatment with tolcapone, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with tolcapone such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing tolcapone 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 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.
What might happen if I take too much Tolcapone?
The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa co-administration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 mcg /mL (compared to 3 mcg /mL and 6 mcg /mL with 100 mg and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.
The threshold for the lethal plasma concentration for tolcapone based on animal data is >100 mcg/mL. Respiratory difficulties were observed in rats at high oral (gavage) and intravenous doses and in dogs with rapidly injected intravenous doses.
Hospitalization is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
How should I store and handle Tolcapone?
Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Store at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F) Protect from freezing. Avoid excessive heat.Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.Preparation for intravenous administration:Tolcapone tablets USP, 100 mg is supplied as peach colored, film-coated irregular hexagon shape deep convex tablets, debossed with “EP”on one side and “370” on the other side . Tolcapone Tablets USP, 100 mg: bottles of 90 (NDC 49884-254-09). Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Par PharmaceuticalPar Formulations Private Limited,Tolcapone tablets USP, 100 mg is supplied as peach colored, film-coated irregular hexagon shape deep convex tablets, debossed with “EP”on one side and “370” on the other side . Tolcapone Tablets USP, 100 mg: bottles of 90 (NDC 49884-254-09). Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Par PharmaceuticalPar Formulations Private Limited,Tolcapone tablets USP, 100 mg is supplied as peach colored, film-coated irregular hexagon shape deep convex tablets, debossed with “EP”on one side and “370” on the other side . Tolcapone Tablets USP, 100 mg: bottles of 90 (NDC 49884-254-09). Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Par PharmaceuticalPar Formulations Private Limited,
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Mechanism of Action:
Tolcapone is a selective and reversible inhibitor of catechol--methyltransferase (COMT).
In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. 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, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (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.
COMT Activity in Erythrocytes:
O
Effect on the Pharmacokinetics of Levodopa and its Metabolites:
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:
Absorption:
Distribution:
Metabolism and Elimination:
O
N
Special Populations:
Hepatic Impairment:
Renal Impairment:
See PRECAUTIONS
The effectiveness of tolcapone 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.
*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.
Effects on “Off” time and levodopa dose did not differ by age or sex.
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:
*Compared to placebo. Nominal p values are not adjusted for multiple comparisons.Effects on Activities of Daily Living did not differ by age or sex.
Non-Clinical Toxicology
Tolcapone tablets are contraindicated in patients with liver disease, inpatients who were withdrawn from tolcapone because of evidence of tolcapone–induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.Tolcapone is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication (see PRECAUTIONS:
(SEE BOXED WARNING) Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections)
Tolcapone therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS:
Patients who develop evidence of hepatocellular injury while on tolcapone and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone 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 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
Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
Falling Asleep During Activities of Daily Living and Somnolence
Tolcapone increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products . 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, 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 treatment (Tolcapone 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 and 0 % of patients treated with 100 mg tolcapone 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.
Before initiating treatment with tolcapone, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with tolcapone such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing tolcapone 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 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.
Protein Binding:
Drugs Metabolized by Catechol-O-Methyltransferase (COMT):
Effect of Tolcapone on the Metabolism of Other Drugs:
Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are co-administered.
Drugs That Increase Catecholamines:
When tolcapone was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson’s disease patients being treated with tolcapone and levodopa/carbidopa. In clinical trials, patients receiving tolcapone/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).
Hypotension/Syncope:
In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension. In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg tolcapone tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg tolcapone tid, respectively, withdrawing from the trials prematurely. Discontinuing tolcapone for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of tolcapone, it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg tolcapone tid groups. Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite). No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown. It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples). In clinical trials, hallucinations developed in approximately 5% of patients treated with placebo, compared to 8% and 10% of patients treated with 100 mg or 200 mg three times per day, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3% of patients treated with placebo, compared to 1.4% and 1.0% of patients treated with tolcapone 100 mg or 200 mg tolcapone three times per day, respectively. Hallucinations led to hospitalization in 0.0% of patients in the placebo group, compared to 1.7% and 0.0% of patients treated with 100 mg or 200 mg tolcapone three times per day, respectively.
In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming.The incidence of hallucination may be increased in elderly patients over 75 years treated with tolcapone . Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during tolcapone treatment or after starting or increasing the dose of tolcapone. Other drugs prescribed to improve the symptoms of Parkinson’s disease may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with tolcapone because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of tolcapone. Tolcapone may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. Dyskinesia was the most common adverse reaction observed in controlled trials and developed in approximately 20% of patients treated with placebo, compared to 42% and 51% of patients treated with tolcapone 100 mg or 200 mg three times daily, respectively. The rates of withdrawal for dyskinesia were 0.0% in the placebo group, compared to 0.3% and 1.0% in the groups receiving tolcapone 100 mg or 200 mg three times a day, respectively. Reports suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. These reports are associated with patients taking tolcapone in conjunction with carbidopa/levodopa, as well as other medications that increase central dopaminergic tone and that are used to treat patients with Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with tolcapone. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking tolcapone Cases of severe rhabdomyolysis, with one case of multi-organ system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, tolcapone played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in and (see PRECAUTIONS: ). No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution (see CLINICAL PHARMACOLOGY: and DOSAGE AND ADMINISTRATION). When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments that would confirm the theory have not been conducted. Because of the risk of liver injury, tolcapone therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction. The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg tolcapone tid, respectively. The etiology of the increase with tolcapone has not always been explained (for example, by urinary tract infection or warfarin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg tolcapone tid, respectively. The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone. In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. It is difficult to determine if tolcapone played a role in the pathogenesis of these events because these patients received several concomitant medications affecting the central nervous system such as monoaminergic (i.e., MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic agents. Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., tolcapone) that increase dopaminergic activity can cause them is unknown. Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion). For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using tolcapone for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
ADVERSE REACTIONS: Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. All 3 cases were reported within the first six months of initiation of treatment with tolcapone. Analysis of the laboratory monitoring data in over 3,400 tolcapone-treated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with tolcapone.
Effects of Gender on Adverse Reactions:
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. 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. depression, hypesthesia, tremor, speech disorder, vertigo, emotional lability; 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; : antisocial reaction, delirium, encephalopathy, hemiplegia, meningitis. — tooth disorder; dysphagia, gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue disorder, rectal disorder; : cholecystitis, duodenal ulcer, gastrointestinal carcinoma, stomach atony. — flank pain, accidental injury, abdominal pain, infection; hernia, pain, allergic reaction, cellulitis, infection fungal, viral infection, carcinoma, chills, infection bacterial, neoplasm, abscess, face edema; death. — palpitation; : 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; arteriosclerosis, cardiovascular disorder, pericardial effusion, thrombosis. — myalgia; tenosynovitis, arthrosis, joint disorder. urinary incontinence, impotence; prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; bladder calculus, ovarian carcinoma, uterine hemorrhage. bronchitis, pharyngitis; cough increased, rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup; apnea, hypoxia, lung edema. — rash; herpes zoster, pruritus, seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder, furunculosis, herpes simplex, urticaria. tinnitus; diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; glaucoma. edema, hypercholesteremia, thirst, dehydration. anemia; leukemia, thrombocytopenia. diabetes mellitus. surgical procedure.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).