1) The following adverse effects have been reported following treatment with COMT inhibitors: Nausea, vomiting, diarrhea, constipation, abdominal pain, anorexia, xerostomia, urine discoloration, orthostatic hypotension, syncope, dyskinesia, dystonia, akathisia, insomnia, drowsiness, headache, confusion, dizziness, hallucinations, increased sweating, rhabdomyolysis, paresthesia, dyspnea, sleep disorder, excessive dreaming, and elevated liver enzymes. Fatal liver damage has been reported following therapeutic use of tolcapone. A neuroleptic malignant syndrome-like complex has been reported in association with the abrupt dose reduction or withdrawal of these agents.

1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. In a study, nausea, vomiting, and dizziness occurred in elderly volunteers after ingesting 800 mg 3 times daily of tolcapone. In studies, abdominal pain and loose stools were the most commonly reported adverse effects in patients receiving entacapone 800 mg 3 times daily for 7 days.

1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Manage mild hypotension with IV fluids.

1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids, dopamine, or norepinephrine. NOTE: Vasopressors should only be used with caution in patients with symptomatic hypotension unresponsive to fluids and supine position, as COMT inhibitors may interfere with the metabolism of agents such as dopamine and norepinephrine and cause exaggerated or prolonged response. Manage dystonic reactions with anticholinergic agents.

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the risk of aspiration secondary to CNS depression and dyskinesias.
2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to protect airway.

1) Insure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.

1) None.

1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine. NOTE: Vasopressors should only be used with caution in patients with symptomatic hypotension unresponsive to fluids and supine position, as COMT inhibitors may interfere with the metabolism of agents such as dopamine and norepinephrine and cause exaggerated or prolonged response.

1) ADULTS: Benztropine 1 to 2 mg IV or diphenhydramine 1 mg/kg/dose IV over 2 minutes. CHILDREN: Diphenhydramine 1 mg/kg/dose IV over 2 minutes (maximum 5 mg/kg/day or 50 mg/m(2)/day).

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.

1) Hemodialysis is unlikely to be of benefit due to the high protein binding of the COMT inhibitors.

1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.
3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.

1) ENTACAPONE: rapidly absorbed after oral use; systemic availability is 29% to 46%; Tmax: 30 to 45 min. Protein binding: 98%; Vd: 0.3 L/kg. Metabolism: primarily metabolized in the liver to glucuronide conjugates. Excretion: renal: about 10% excreted into the urine as glucuronides of entacapone and its Z-isomer. Feces: 90%. Elimination half-life: 1.59 to 3.44 hours after oral use and 0.5 hour after IV administration. TOLCAPONE: rapidly absorbed with an absolute oral bioavailability of approximately 65%. Protein binding: greater than 99.9%; Vd: 0.15 L/kg. Metabolism: Methylated by COMT to 3-O-methyltolcapone (an inactive metabolite), oxidized by cytochrome P450 isoenzymes to an alcohol and subsequently oxidized to a carboxylic acid. Excretion: renal: 60% excreted in the urine. Feces: 40%. Elimination half-life: 2 to 3 hours.

1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), dystonia or dyskinesia (eg, antipsychotics, neuroleptics), or hepatotoxicity (eg, alcohol, acetaminophen).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) ANIMAL STUDIES - Tolcapone, when administered alone, was NOT teratogenic in doses up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 and 15 times the recommended daily clinical dose of 600 mg, on a mg/m(2) basis, respectively) (Prod Info Tasmar(R), tolcapone tablets, 1998).

1) RABBITS - An increased rate of abortion occurred in rabbits following tolcapone administration at doses of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m(2) basis or greater) (Prod Info Tasmar(R), tolcapone tablets, 1998).

1) RATS - Tolcapone was excreted into maternal rat milk (Prod Info Tasmar(R), tolcapone tablets, 1998).

1) RATS - Tolcapone did NOT impair fertility in rats at doses up to 300 mg/kg/ day (5.7 times the human dose on a mg/m(2) basis) (Prod Info Tasmar(R), tolcapone tablets, 1998).

1) Orthostatic hypotension, a dopaminergic effect, has been reported following tolcapone and entacapone administration (Baas et al, 1997; Kieburtz et al, 1997; Limousin et al, 1995) . The occurrence of orthostatic hypotension may increase due to the increased bioavailability of levodopa by the administration of tolcapone or entacapone (Prod Info COMTAN(R) oral tablets, 2010; Ruottinen & Rinne, 1996a).
2) Orthostatic hypotension has been reported during double-blind, placebo-controlled trials in 17% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, compared with 14% of patients in the placebo group (Prod Info TASMAR(R) oral tablets, 2006).

1) WITH THERAPEUTIC USE

1) Shortness of breath has been reported following tolcapone administration, 100 to 200 mg 3 times daily (Prod Info TASMAR(R) oral tablets, 2006a; Baas et al, 1997) and after the initiation of entacapone therapy (Kieburtz et al, 1997).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) COMT inhibitors may potentiate the dopaminergic side effects of levodopa therapy, when given in combination with levodopa/carbidopa therapy, and thereby may cause and/or exacerbate preexisting dyskinesia (Baas et al, 1997).
2) In double-blind, placebo-controlled trials of entacapone or placebo added to a levodopa-based therapy, dyskinesia was reported in 25% of entacapone-treated patients (n=603), compared with 15% in the placebo group (n=400). Entacapone can enhance dopaminergic adverse effects of levodopa and may lead to, or worsen, dyskinesias (Prod Info COMTAN(R) oral tablets, 2010).
3) Dyskinesia has been reported during double-blind, placebo-controlled trials in 42% and 51% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 20% of patients in the placebo group (Prod Info TASMAR(R) oral tablets, 2006).
4) Rajput et al (1997) conducted a randomized, placebo-controlled trial to determine the efficacy of tolcapone in the "wearing-off" phenomenon associated with levodopa therapy. Dyskinesias developed or worsened in 18% of patients receiving placebo, in 51% of patients receiving tolcapone 100 mg 3 times daily, and in 64% of patients receiving tolcapone 200 mg 3 times daily. The dyskinesias primarily occurred within the first 30 days of the study (Rajput et al, 1997).
5) Coadministration of entacapone with levodopa caused dyskinesias to appear in 53 of 55 patients during the first 8 weeks of a trial, conducted to determine the efficacy of entacapone. The dyskinesias resolved in 17 of the 53 patients during the first 8 weeks after modification of the levodopa dosage (Kieburtz et al, 1997).

1) During a tolcapone placebo-controlled trial, dystonia occurred in 17%, 19%, and 22% of patients after ingestion of placebo, 100 mg of tolcapone 3 times daily, and 200 mg of tolcapone 3 times daily, respectively (Prod Info TASMAR(R) oral tablets, 2006a).
2) Dystonia has been reported during double-blind, placebo-controlled trials in 19% and 22% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 17% of patients in the placebo group. Dystonia develops more often in patients younger than 75 years (Prod Info TASMAR(R) oral tablets, 2006).

1) Insomnia was reported as a dopaminergic effect following therapeutic administration of tolcapone (Baas et al, 1997; Rajput et al, 1997).

1) Somnolence, a dopaminergic effect, occurred with tolcapone therapy, 100 to 200 mg 3 times daily (Baas et al, 1997; Rajput et al, 1997) and with entacapone therapy (Kieburtz et al, 1997).
2) Dingemanse et al (1995) conducted a study to determine the safety and efficacy of tolcapone. One subject reported mild somnolence following administration of 400 mg of tolcapone (Dingemanse et al, 1995a).
3) Somnolence has been reported during double-blind, placebo-controlled trials in 18% and 14% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 13% of patients in the placebo group. Somnolence was more likely to develop in females (Prod Info TASMAR(R) oral tablets, 2006).

1) Headaches are one of the most common nondopaminergic effects that occurred following therapeutic administration of tolcapone and entacapone (Baas et al, 1997; Kaakkola et al, 1994) .
2) Headache has been reported during double-blind, placebo-controlled trials in 10% and 11% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 7% of patients in the placebo group (Prod Info TASMAR(R) oral tablets, 2006).

1) Akathisia has been reported in 5% and 7% of patients who ingested 100 mg and 200 mg 3 times daily of tolcapone, respectively, during a tolcapone efficacy study (Baas et al, 1997).

1) Dingemanse et al (1995) reported that one patient, involved in a tolcapone efficacy study, experienced mild paresthesias in the legs after ingesting 10 mg of tolcapone (Dingemanse et al, 1995a).

1) There have been several reported cases of a complex similar to neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness) that occurred following dose reduction or abrupt withdrawal of tolcapone therapy. In several of the cases, the serum creatine kinase level was also elevated. Although the majority of patients have recovered, 1 fatality did occur (Iwuagwu et al, 2000).
2) Several cases of signs and symptoms resembling neuroleptic malignant syndrome (eg, elevated temperature, muscular rigidity, altered consciousness, and elevated creatine phosphokinase) have been reported with dose reduction or abrupt discontinuation of entacapone and other dopaminergic therapies. These cases have been complicated and no causal relationship has been determined (Prod Info COMTAN(R) oral tablets, 2010).
3) Signs and symptoms resembling neuroleptic malignant syndrome (eg, elevated temperature, muscular rigidity, and altered consciousness) have been reported with tolcapone and other dopaminergic therapies in association with abrupt withdrawal or lowering of the dose. Elevated creatine phosphokinase (CPK) was also seen. Of 4 cases reported in clinical trials during development, 3 patients recovered over a period of 2 to 6 weeks, but 1 patient died. Cases have been reported rarely postmarketing. These cases have been complicated and no causal relationship to tolcapone has been determined. Caution is advised when using combinations of medications with tolcapone that may also affect monoaminergic and anticholinergic systems in the brain (Prod Info TASMAR(R) oral tablets, 2006).

1) Increased confusion was reported in 3 patients with severe Parkinson disease that were started on tolcapone therapy. The confusion resolved within 24 hours of cessation of the tolcapone (Henry & Wilson, 1998).
2) There was no difference in the incidence of confusion between tolcapone and placebo (Prod Info TASMAR(R) oral tablets, 2006a; Guay, 1999).
3) Confusion has been reported during double-blind, placebo-controlled trials in 11% and 10% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 9% of patients in the placebo group (Prod Info TASMAR(R) oral tablets, 2006).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) Increases of more than 3 times the upper limit of normal in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 1% and 3% of patients receiving tolcapone 100 mg 3 times daily (TID) and 200 mg TID, respectively. Increases of more than 8 times the upper limit of normal of ALT and AST occurred in 0.3% and 0.7% of patients receiving tolcapone 100 mg TID, and 200 mg TID, respectively, leading to discontinuation in 0.3% and 1.7% of patients, respectively. There was a greater frequency of elevated liver enzymes in females (5%) compared with males (2%). Elevated enzymes were frequently associated with diarrhea and occurred within 6 weeks to 6 months of the initiation of tolcapone. Upon tolcapone discontinuation, liver enzymes started to decrease within 2 to 3 weeks and returned to baseline in some patients after 1 to 2 months (Prod Info TASMAR(R) oral tablets, 2006a).
2) Rajput et al (1997) reported elevated AST and ALT concentrations, during a tolcapone efficacy study, in 3 patients who ingested tolcapone 100 mg 3 times daily, and in 2 patients who ingested tolcapone 200 mg 3 times daily. One of the patients, in the 200 mg tolcapone group, withdrew from the study because the hepatic enzyme levels were 3 to 5 times the upper limit of normal (Rajput et al, 1997).
3) CASE REPORT: A 76-year old patient with Parkinson disease developed hepatotoxicity and hepatic dysfunction within 3 weeks of the addition of entacapone 200 mg 5 times per day to her established drug regimen. Following discontinuation of entacapone, liver dysfunction resolved (Fisher et al, 2002).

1) During postmarketing use, severe hepatocellular injury cases, including fulminant liver failure resulting in death, were observed. Three cases of fatal fulminant hepatic failure were reported from more than 40,000 patient years of worldwide use. Hepatic failure occurred within the first 6 months of therapy. In general, increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), when present, occurred within the first 6 months of treatment based on an analysis of the laboratory monitoring data in over 3400 tolcapone-treated patients participating in clinical trials (Prod Info TASMAR(R) oral tablets, 2006a).
2) CASE REPORT: A 74-year-old woman presented to the hospital with confusion, frequent episodes of falls, and jaundice 9 weeks after initiating tolcapone therapy, 100 mg twice daily, for treatment of Parkinson disease. Laboratory tests showed elevated liver enzyme levels and a liver biopsy revealed centrilobular necrosis with inflammatory infiltrates. The patient died of liver failure 14 days later, despite discontinuation of tolcapone (Assal et al, 1998).

1) A transient orange discoloration of urine has been reported following COMT inhibitor therapy (Prod Info COMTAN(R) oral tablets, 2010; Kieburtz et al, 1997; Rajput et al, 1997; Keranen et al, 1994; Merello et al, 1994; Kaakkola et al, 1990) .
2) In double-blind, placebo-controlled trials of entacapone or placebo added to a levodopa-based therapy, urine discoloration was reported in 10% of entacapone-treated patients (n=603), compared with 0% in the placebo group (n=400) (Prod Info COMTAN(R) oral tablets, 2010).
3) Urine discoloration has been reported during double-blind, placebo-controlled trials in 2% and 7% of patients receiving tolcapone 100 mg (n=296), or 200 mg (n=298) 3 times daily, respectively, compared with 1% of patients in the placebo group(Prod Info TASMAR(R) oral tablets, 2006).

1) Epidemiologic studies indicate patients with Parkinson disease are at a 2- to approximately 6-fold higher risk of developing melanoma than the general population, but the causality (eg, Parkinson disease versus the drugs used to treat it) is unknown (Prod Info TASMAR(R) oral tablets, 2013).

1) Based on preliminary data from the Stalevo Reduction in Dyskinesia Evaluation - Parkinson Disease (STRIDE-PD) trial, the fixed combination of carbidopa/levodopa/entacapone may lead to an increased incidence of prostate cancer. In a randomized, multicenter, double-blind, controlled trial of men with Parkinson disease (average age, 60 years), prostate cancer was reported in 3.7% (95% CI, 1.69% to 6.86%) of patients who received carbidopa/levodopa/entacapone (n=245) compared with 0.9% of patients who received carbidopa/levodopa (n=222), resulting in an incidence of 14 versus 3.2 cases per 1000 patient-years, respectively. The odds ratio for prostate cancer in men treated with carbidopa/levodopa/entacapone was 4.19 (95% CI, 0.9 to 19.63). The mean duration of therapy prior to prostate cancer diagnosis was 664 days (range, 148 to 949 days). The US Food and Drug Administration is currently evaluating the data and makes no conclusions or recommendations regarding the use of carbidopa/levodopa/entacapone (US Food and Drug Administration and US Food and Drug Administration, 2010).

1) The carcinogenic potential of the carbidopa/levodopa/entacapone combination has not been evaluated (Prod Info COMTAN(R) oral tablets, 2016; Prod Info STALEVO(R) oral tablets, 2008).
2) The carcinogenic potential of tolcapone administered with levodopa/carbidopa has not been evaluated (Prod Info TASMAR(R) oral tablets, 2013).

1) There was an increased incidence of uterine adenomas in female rats given tolcapone 450 mg/kg/day (26.4 times the human exposure) (Prod Info TASMAR(R) oral tablets, 2013).

1) RATS: A significantly increased incidence of tubular cell carcinomas was noted in male rats administered tolcapone 450 mg/kg/day for 2 years (Prod Info TASMAR(R) oral tablets, 2013).
2) RATS: An increased incidence of renal tubular adenomas and carcinomas was found in male rats administered entacapone 400 mg/kg/day (AUC approximately 20 times higher than the maximum recommended daily human exposure) by oral gavage for 2 years (Prod Info COMTAN(R) oral tablets, 2016; Prod Info STALEVO(R) oral tablets, 2008).
3) MICE: Carcinogenicity data were inconclusive in mice administered entacapone by oral gavage at 20, 100, or 600 mg/kg/day (0.05, 0.3, and 2 times the maximum recommended daily human dose on a mg/m(2) basis) due to a high incidence of premature mortality reported with the highest dose (Prod Info STALEVO(R) oral tablets, 2008).

1) No increase in tumors were observed in mice given oral doses of entacapone up to 4 times the exposure at the maximum recommended human dose in carcinogenicity studies (Prod Info COMTAN(R) oral tablets, 2016).

A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.

A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) Monitor vital signs and perform neurologic exam.
2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
3) Monitor liver enzymes after significant overdose.
4) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
5) Serum concentrations of COMT inhibitors are not widely available or clinically useful in managing overdose.

1) ADULT
2) CHILDREN

1) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and place in supine position. Consider central venous pressure monitoring to guide further fluid therapy. Vasopressors should only be used with caution in patients with symptomatic hypotension unresponsive to fluids and Trendelenburg position, as COMT inhibitors may interfere with the metabolism of agents such as dopamine and norepinephrine and cause an exaggerated or prolonged response.
2) DOPAMINE
3) NOREPINEPHRINE

1) NMS may develop after abrupt cessation of COMT inhibitors. It is not expected after acute overdose.
2) May be successfully managed with diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).
3) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with DANTROLENE (mean 1.15 days) or BROMOCRIPTINE (1.03 days) than with supportive measures alone (6.8 days).
4) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases (Sakkas et al, 1991).

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

1) SPECIFIC SUBSTANCE

1) LD50- (INTRAPERITONEAL)MOUSE:

1) LD50- (INTRAPERITONEAL)MOUSE:

1) LD50- (ORAL)MOUSE:
2) LD50- (ORAL)RAT: