a) GENERIC: Oral tablet - (carbidopa-levodopa) 10 mg-100 mg; 25 mg-100 mg; 25 mg-250 mg; oral tablet, disintegrating - (carbidopa-levodopa) 10 mg-100 mg; 25 mg-100 mg; 25 mg-250 mg; oral tablet, extended release - (carbidopa-levodopa) 25 mg-100 mg; 50 mg-200 mg
b) PARCOPA: Oral tablet, disintegrating - (carbidopa-levodopa) 10 mg-100 mg; 25 mg-100 mg; 25 mg-250 mg
c) SINEMET 10-100: Oral tablet - (carbidopa-levodopa) 10 mg -100 mg
d) SINEMET 25-100: Oral tablet - (carbidopa-levodopa) 25 mg-100 mg
e) SINEMET 25-250: Oral tablet - (carbidopa-levodopa) 25 mg-250 mg
f) SINEMET CR: Oral tablet, extended release - (carbidopa-levodopa) 25 mg-100 mg; 50 mg-200 mg

1) COMMON: Nausea, dyskinesia (eg, choreiform, dystonia, facial tics, grimacing, head bobbing, torticollis, and choreoathetosis). OTHER EFFECTS: Anorexia, vomiting, somnolence, agitation, diaphoresis, insomnia, anxiety, confusion, postural hypotension, dizziness, hypertension, rash, delirium, hallucinations, psychosis, respiratory dyskinesias, and Henoch-Schonlein purpura. A constellation of symptoms resembling neuroleptic malignant syndrome has been described following withdrawal of levodopa/carbidopa. Symptoms reported include fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, mental status changes, autonomic dysfunction, tachycardia, tachypnea, sweating, and hyper- or hypotension.

1) The most common signs/symptoms seen following acute overdose include confusion, agitation, diaphoresis, insomnia, anxiety, and excessive motor activity. Other effects reported after acute overdose have included nausea, vomiting, sinus tachycardia, postural hypotension, restlessness, hypertension, dyskinesias, confusion, delirium, hallucinations, psychosis, xerostomia, urinary retention, mydriasis, increased CK, myoglobinuria, rhabdomyolysis, and respiratory dyskinesias.

1) Malignant hyperthermia has occurred following withdrawal of therapy.

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Control agitation and confusion with benzodiazepines.

1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat dystonias and dyskinetic movements with diazepam, diphenhydramine, or benztropine. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. Treat neuroleptic malignant syndrome with benzodiazepines, bromocriptine, consider dantrolene, as well as cooling and supportive measures.

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended.
2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe toxicity (eg, excessive drowsiness, severe delirium, or hyperthermia).

1) None.

1) Dystonias may respond to diazepam, diphenhydramine or benztropine. ADULT: Benztropine is dosed at 1 to 4 mg IV or IM, maximum 6 mg/day. Diphenhydramine is dosed at 25 to 50 mg IV over 2 minutes. PEDIATRIC: Diphenhydramine: 1.25 mg/kg/dose IV over 2 minutes.

1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.

1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.

1) Sedate with benzodiazepines as needed; large doses may be required. Provide a quiet environment.

1) Oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider IV dantrolene in severe cases.

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) No data are currently available, however, due to the large volume of distribution of levodopa and rapid metabolism, it is doubtful that significant amounts would be removed by dialysis.

1) HOME CRITERIA: Patients who are asymptomatic after inadvertent ingestion can be managed at home.
2) OBSERVATION CRITERIA: Symptomatic patients and those with deliberate ingestions should be sent to a medical facility for evaluation and treatment. Peak concentrations of sustained-release formulation is reached 2 hours after ingestion as compared with 0.5 hours after an immediate-release formulation. Patients that have ingested a sustained-release product have the potential to manifest symptoms in a delayed/prolonged fashion and should be observed for 4 to 8 hours.
3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.

1) Bioavailability: immediate release: 80% to 90%; sustained release: 70% to 75%. Tmax: Immediate-release: mean, 0.5 hours. Tmax: Sustained-release tablets: mean, 2 hours. Protein binding: not bound to plasma proteins. Vd: 0.6 L/kg (elderly subjects). Metabolism: Levodopa is metabolized by decarboxylation (via levodopa decarboxylase) to dopamine in the gut, liver, and kidney and by o-methylation, transamination, and oxidation. Excretion: 70% to 80% of levodopa is excreted in the urine in the form of metabolites, within 24 hours. Elimination half-life: 1.5 hours; metabolite 3-O-methyldopa: 15 hours.

1) Includes other agents that may cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), hypertension (eg, amphetamine), dystonia or dyskinesias (eg, antipsychotics, neuroleptics), or neuroleptic malignant syndrome (eg, antipsychotics, neuroleptics).

1) Malignant hyperthermia has occurred following withdrawal of therapy.

1) MALIGNANT HYPERTHERMIA has been reported following withdrawal of levodopa therapy (Henderson & Wooten, 1981; Sechi et al, 1984) Toru et al, 1981; (Gibb & Griffith, 1986).

1) Bilateral maximally dilated pupils, with absent light reaction, were reported approximately 90 minutes following an overdose of 30 tablets of carbidopa/levodopa (50 mg/200 mg) (Stuerenburg & Schoser, 1999).
2) MYDRIASIS: Mydriasis developed in a 55-year-old man 2.5 hours after ingesting 89 tablets of Sinemet(R) 50/200 (a controlled-release formulation; 17.8 g of levodopa, 4.45 g of carbidopa) (Delmas et al, 2008).

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) Carbidopa concentrations in fetal tissue appeared to be minimal according to individual reports (Prod Info LODOSYN(R) oral tablets, 2014).

1) CARBIDOPA

1) Carbidopa has a FDA pregnancy category of C (Prod Info LODOSYN(R) oral tablets, 2014).

1) Individual cases of levodopa use during pregnancy shows the drug crosses the human placental barrier, enters the fetus, and is metabolized (Prod Info LODOSYN(R) oral tablets, 2014).

1) CARBIDOPA

1) CARBIDOPA

1) Because many drugs are excreted into human milk and because the potential for serious adverse reactions exists in nursing infants, either discontinue breastfeeding or discontinue carbidopa, considering the importance of the drug to the mother (Prod Info LODOSYN(R) oral tablets, 2014).

1) CARBIDOPA

1) Based on preliminary data from the Stalevo Reduction in Dyskinesia Evaluation - Parkinson's 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% confidence interval (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 rate of 14 vs 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 combination of carbidopa/levodopa/entacapone has not been evaluated (Prod Info STALEVO(R) oral tablets, 2008).

1) RATS: An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with entacapone doses of 400 mg/kg/day (AUC approximately 20 times higher than the maximum recommended daily human exposure) by oral gavage for 2 years (Prod Info STALEVO(R) oral tablets, 2008).
2) 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) RATS: No evidence of carcinogenicity was found in rats administered approximately 2 times and 4 times the maximum recommended daily human dose of carbidopa and levodopa, respectively, during a 2-year bioassay of carbidopa and levodopa combination (Prod Info SINEMET(R) oral tablets, 2013; Prod Info STALEVO(R) oral tablets, 2008).
2) RATS: No significant difference in mortality or neoplasia was detected between treated and control rats in a 96-week study of oral carbidopa at doses of 25, 45, or 135 mg/kg/day (Prod Info LODOSYN(R) oral tablets, 2014).
3) RATS: No effect on mortality or incidence and type of neoplasia was detected between treated and control rats in a 106-week study of oral carbidopa/levodopa combinations at doses of 10/20, 10/50, or 10/100 mg/kg/day (Prod Info LODOSYN(R) oral tablets, 2014).

1) Serum catecholamine levels may be elevated.

1) Urinary catecholamine levels may be elevated.

A) Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.

A) Patients who are asymptomatic after inadvertent ingestion can be managed at home.

A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

A) Symptomatic patients and those with deliberate ingestions should be sent to a medical facility for evaluation and treatment. Peak concentrations of sustained-release formulation is reached 2 hours after ingestion as compared with 0.5 hours after an immediate-release formulation. Patients that have ingested a sustained-release product have the potential to manifest symptoms in a delayed/prolonged fashion and should be observed for 4 to 8 hours.
B) A 55-year-old man ingested 89 tablets of Sinemet(R) 50/200 (a controlled-release formulation; 17.8 g of levodopa, 4.45 g of carbidopa). The initial peak of dopamine was noted 14 hours postingestion, followed by a progressive decline and then a second peak at 38 hours after ingestion. The initial peak of noradrenalin was observed 20 hours postingestion, followed by a progressive decline and then a second shorter peak at 38 hours after the ingestion. Ten hours postingestion, the adrenalin peak concentration was 240 ng/L, which quickly declined to the reference range. In this patient, symptoms reappeared 48 hours postingestion and 10 hours after the second peaks of dopamine and noradrenalin. The authors concluded that there was no correlation between the intensity of the clinical signs and the blood concentrations of dopamine and noradrenalin (Delmas et al, 2008).

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) No specific laboratory tests are necessary unless otherwise clinically indicated.
2) Monitor vital signs and mental status following significant overdose.
3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
4) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.

1) ADULT
2) CHILDREN
3) AMANTADINE: In a randomized, single-center, double-masked, placebo-controlled, 3-week crossover study (n=24), amantadine therapy (100 mg twice daily) significantly reduced the total dyskinesia score (Goetz scale) by 24% compared with placebo (p=0.004). Furthermore, the maximal dyskinesia score was significantly decreased by 17% in the amantadine group compared with placebo (p=0.02) (Pahwa et al, 2006).
4) PROPRANOLOL: Propranolol in doses up to 60 mg daily for 5 to 6 weeks resulted in a mean 40% improvement in dystonic reactions in 7 patients. Four patients with ballistic or choreic dyskinesias showed the greatest improvement (up to 78%), while the one patient without benefit was characterized as pure dystonia. Daily life was dramatically improved in responding patients, with fewer falls due to motor disability; withdrawal of adjunctive apomorphine; and an increase in duration of "on" time noted. No loss of parkinsonian motor control was reported subjectively or objectively; blood pressure and heart rate were not adversely effected at the low doses of propranolol used (Carpentier et al, 1996).
5) FLUOXETINE: Fluoxetine 20 mg daily for 11 days improved the dystonic response to apomorphine challenge (particularly those arising in the trunk and lower limbs) by approximately 50% in 7 chronic Parkinson patients (Durif et al, 1995).
6) Other treatments which have been tried, but have not been proven clinically efficacious, include deanol (Miller, 1974) and pyridoxine (10 to 15 milligrams intravenously) (Bianchine, 1980; Jameson, 1970).

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS
4) SODIUM NITROPRUSSIDE/DOSE
5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
8) PHENTOLAMINE/INDICATIONS
9) PHENTOLAMINE/ADULT DOSE
10) PHENTOLAMINE/PEDIATRIC DOSE
11) PHENTOLAMINE/ADVERSE EFFECTS
12) CAUTION
13) NITROGLYCERIN/INDICATIONS
14) NITROGLYCERIN/ADULT DOSE
15) NITROGLYCERIN/PEDIATRIC DOSE

1) SUMMARY
2) DOPAMINE
3) NOREPINEPHRINE

1) Sedate with benzodiazepines as needed; large doses may be required. Provide a quiet environment.
2) INDICATION
3) DIAZEPAM DOSE
4) LORAZEPAM DOSE
5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.

1) Neuroleptic malignant syndrome due to levodopa withdrawal may be successfully managed with diphenhydramine, oral bromocriptine, IV benzodiazepines, conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992). Dantrolene may be considered in severe cases.
2) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of NMS should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002). Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).
3) BROMOCRIPTINE DOSE: 5 mg 3 times a day orally (Mueller et al, 1983).
4) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg IV (Barkin, 1992).
5) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg IV every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).
6) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).
7) 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). The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
8) 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. Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17). In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations (Sakkas et al, 1991).
9) RIGIDITY: Was slowly responsive to dantrolene 25 milligrams three times daily in a 76-year-old with NMS (Reutens 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) INADEQUATE REDUCTION IN NAUSEA/VOMITING: Initial, 25 mg orally with first carbidopa/levodopa dose of the day; additional 12.5 to 25 mg may be given during the day with each dose of carbidopa/levodopa; MAX total carbidopa dose, 200 mg/day (Prod Info LODOSYN(R) oral tablets, 2014).
2) INDIVIDUAL TITRATION OF CARBIDOPA AND LEVODOPA: Initial, 25 mg orally 3 or 4 times daily concomitantly with levodopa; give the 2 drugs at same time; initiate with 20% to 25% of the previous or recommended levodopa daily dose when given without carbidopa; initiate at least 12 hours after the last dose of levodopa (Prod Info LODOSYN(R) oral tablets, 2014).
3) MAXIMUM DOSE: 200 mg/day (Prod Info LODOSYN(R) oral tablets, 2014).

1) IMMEDIATE-RELEASE TABLETS: Initial, 1 carbidopa/levodopa combination tablet (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg) orally 3 to 4 times daily; titrate up to 8 tablets daily (Prod Info SINEMET(R) oral tablets, 2013).
2) IMMEDIATE-RELEASE ORAL DISINTEGRATING TABLETS: Initial, 1 carbidopa/levodopa combination tablet (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg) orally 3 to 4 times daily; titrate up to 8 tablets daily; place on top of tongue; handle with dry hands (Prod Info PARCOPA(R) oral disintegrating tablets, 2011).
3) ENTERAL SUSPENSION: Each single-use cassette contains about 100 mL of suspension, containing 4.63 mg carbidopa and 2 mg levodopa per mL of enteral suspension. The maximum daily dose of 2000 mg of levodopa (one cassette per day) should be administered over 16 hours (Prod Info DUOPA enteral suspension, 2015).
4) SUSTAINED-RELEASE TABLETS: Initial, 1 carbidopa/levodopa combination tablet (25 mg/100 mg or 50 mg/200 mg) orally 2 or 3 times daily; titrate to 400 to 1600 mg of levodopa daily in divided doses; do not chew or crush (Prod Info SINEMET(R) CR oral sustained release tablets, 2013).

1) CASE REPORTS

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