Carbidopa, Levodopa, and Entacapone

Carbidopa, levodopa and entacapone tablets are indicated for the treatment of Parkinson's disease. Carbidopa, levodopa and entacapone tablets can be used:

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

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

• Carbidopa, levodopa and entacapone tablets (12.5 mg per 50 mg per 200 mg)
• Carbidopa, levodopa and entacapone tablets (18.75 mg per 75 mg per 200 mg)
• Carbidopa, levodopa and entacapone tablets (25 mg per 100 mg per 200 mg)
• Carbidopa, levodopa and entacapone tablets (31.25 mg per 125 mg per 200 mg)
• Carbidopa, levodopa and entacapone tablets (37.5 mg per 150 mg per 200 mg)
• Carbidopa, levodopa and entacapone tablets (50 mg per 200 mg per 200 mg)

Carbidopa, levodopa and entacapone tablets are contraindicated in patients:

• Taking nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine). These nonselective MAO inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa, levodopa and entacapone tablets.
• With narrow-angle glaucoma.
• Concomitant use of nonselective monoamine oxidase (MAO) inhibitors ( 4 )
• Narrow-angle glaucoma ( 4 )

The following adverse reactions described in this section are related to at least one of the components of carbidopa, levodopa and entacapone tablets (i.e., levodopa, carbidopa, and/or entacapone) based upon the safety experience in clinical trials (especially pivotal trials) or in postmarketing reports.

• May cause falling asleep during activities of daily living without apparent warning, and daytime drowsiness and somnolence ( 5.1 )
• May cause syncope and hypotension/orthostatic hypotension ( 5.2 )
• May cause or exacerbate dyskinesia ( 5.3 )
• May cause depression and suicidality ( 5.4 )
• May cause hallucinations and/or other psychotic-like behavior ( 5.5 )
• May cause problems with impulse control and compulsive behaviors ( 5.6 )
• Abrupt discontinuation may cause hyperpyrexia and confusion ( 5.7 )
• May cause diarrhea and/or drug-induced colitis ( 5.8 )
• May cause rhabdomyolysis ( 5.9 )

5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients with Parkinson's disease treated with carbidopa, levodopa and entacapone tablets or other carbidopa/levodopa products have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (including the operation of motor vehicles). Some of these episodes resulted in accidents. Although many of these patients reported somnolence while taking entacapone, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported to occur up to one year after initiation of treatment. Somnolence was reported in 2% of patients taking entacapone and 0% in placebo in controlled trials. It is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also 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 and/or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa, levodopa and entacapone tablets. Before initiating treatment with carbidopa, levodopa and entacapone tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase this risk such as use of concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), carbidopa, levodopa and entacapone tablets should ordinarily be discontinued [see Dosage and Administration (2.6) , and Warnings and Precautions (5.7) ]. If the decision is made to continue carbidopa, levodopa and entacapone tablets, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Hypotension, Orthostatic Hypotension and Syncope Reports of syncope were generally more frequent in patients in both treatment groups who had had a prior episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). Hypotension, orthostatic hypotension, and syncope are observed in patients treated with drugs that increase central dopaminergic tone including carbidopa, levodopa and entacapone tablets.

5.3 Dyskinesia Dyskinesia (involuntary movements) may occur or be exacerbated at lower dosages and sooner with carbidopa, levodopa and entacapone tablets than with preparations containing only carbidopa and levodopa. The occurrence of dyskinesias may require dosage reduction. In pivotal trials, the treatment difference incidence of dyskinesia was 10% and for carbidopa-levodopa plus 200 mg entacapone. 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. The treatment difference incidence of study withdrawal for dyskinesia was 1% for carbidopa-levodopa-entacapone.

5.4 Depression and Suicidality All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.

5.5 Hallucinations and/or Psychotic-Like Behavior Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with carbidopa, levodopa, entacapone and carbidopa, levodopa, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the carbidopa, levodopa, entacapone and carbidopa, levodopa, groups, respectively. Agitation occurred in 1% of patients treated with carbidopa, levodopa, entacapone and 0% treated with carbidopa, levodopa.

5.6 Impulse Control and/or Compulsive Behaviors Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications generally used for the treatment of Parkinson's disease and which increase central dopaminergic tone, including entacapone taken with levodopa and carbidopa. In some cases, although not all, these urges were reported to have stopped when the dose of anti-Parkinson medications was reduced or 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 entacapone. Physicians should consider dose reduction or stopping carbidopa, levodopa and entacapone tablets if a patient develops such urges while taking carbidopa, levodopa and entacapone tablets [see Dosage and Administration (2.6) , Warnings and Precautions (5.7) ].

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion Cases of hyperpyrexia and confusion resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reduction or withdrawal of therapy with carbidopa, levodopa and entacapone. However, in some cases, hyperpyrexia and confusion were reported after initiation of treatment with entacapone. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperpyrexia/fever/hyperthermia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension, and abnormal laboratory findings (e.g., creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin). If a patient needs to discontinue or reduce their daily dose of carbidopa, levodopa and entacapone tablets, the dose should be decreased slowly, with supervision from a health care provider [see Dosage and Administration (2.6) ]. Specific methods for tapering entacapone have not been systematically evaluated. […]

The following adverse reactions are discussed in more detail in the Warnings and Precautions sections of labeling:

• Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ]
• Hypotension/Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.2) ]
• Dyskinesia [see Warnings and Precautions (5.3) ]
• Depression and suicidality [see Warnings and Precautions (5.4) ]
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.5) ]
• Impulse Control and/or Compulsive Behaviors [see Warnings and Precautions (5.6) ]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7) ]
• Diarrhea and Colitis [see Warnings and Precautions (5.8) ]
• Rhabdomyolysis [see Warnings and Precautions (5.9) ]
• Vitamin B6 Deficiency and Seizures [see Warnings and Precautions (5.10) ]
• Peptic Ulcer Disease [see Warnings and Precautions (5.13) ] The most common adverse reactions (incidence 3% higher than placebo incidence) are dyskinesias, hyperkinesia, diarrhea, nausea, abdominal pain, vomiting, dry mouth and urine discoloration ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice. Entacapone The most commonly observed adverse reactions (incidence at least 3% greater than placebo incidence) in the double-blind, carbidopa-levodopa-placebo-controlled trials of entacapone (N=1,003 patients) associated with the use of carbidopa-levodopa-entacapone alone and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia, diarrhea, nausea, hyperkinesia, abdominal pain, vomiting, dry mouth, and urine discoloration. The treatment difference incidence for premature study discontinuation for entacapone with levodopa and dopa decarboxylase inhibitor in the double-blind, placebo-controlled trials was 5%. The treatment difference incidence for the most frequent causes of study discontinuation was 2% for diarrhea, and 1% for other specific adverse reactions including psychiatric reasons, dyskinesia/ hyperkinesia, nausea, or abdominal pain. Adverse Reaction Incidence in Controlled Clinical Studies of Entacapone Table 2 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with carbidopa/levodopa and 200 mg of entacapone who participated in the double-blind, placebo-controlled studies, and that were numerically more common in this group than in the carbidopa/levodopa plus placebo group. In these studies, either entacapone or placebo was added to carbidopa/levodopa (or benserazide/levodopa). Table 2: Summary of Patients With Adverse Reactions After Start of Trial Drug Administration At Least 1% in Entacapone Group and Greater Than Placebo SYSTEM ORGAN CLASS Carbidopa/levodopa plus Entacapone Carbidopa/levodopa plus Placebo Adverse Reaction (n=603) % of patients (n=400) % of patients SKIN AND APPENDAGES DISORDERS Sweating Increased 2 1 MUSCULOSKELETAL SYSTEM DISORDERS Back Pain 5 3 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS Dyskinesia 25 15 Hyperkinesia 10 5 Hypokinesia 9 8 Dizziness 8 6 SPECIAL SENSES, OTHER DISORDERS Taste Perversion 1 0 PSYCHIATRIC DISORDERS Anxiety 2 1 Somnolence 2 0 Agitation 1 0 GASTROINTESTINAL SYSTEM DISORDERS Nausea 14 8 Diarrhea 10 4 Abdominal Pain 8 4 Constipation 6 4 Vomiting 4 1 Mouth Dry 3 0 Dyspepsia 2 1 Flatulence 2 0 Gastritis 1 0 Gastrointestinal Disorders NOS 1 0 RESPIRATORY SYSTEM DISORDERS Dyspnea 3 1 PLATELET, BLEEDING AND CLOTTING DISORDERS Purpura 2 1 URINARY SYSTEM DISORDERS Urine Discoloration 10 0 BODY AS A WHOLE-GENERAL DISORDERS Fatigue 6 4 Asthenia 2 1 RESISTANCE MECHANISM DISORDERS Infection Bacterial 1 0

6.2 Postmarketing Experience The following spontaneous reports of adverse events temporally associated with entacapone tablets or carbidopa, levodopa and entacapone tablets have been identified since market introduction and are not listed in Table 2 . Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to entacapone or carbidopa, levodopa and entacapone tablets exposure. Hepatitis with mainly cholestatic features has been reported. Effects of Gender and Age on Adverse Reactions No differences were noted in the rate of adverse reactions attributable to entacapone alone by age or gender.

• Drugs metabolized by COMT: use with caution ( 5.11 , 7.2 )
• Anti-hypertensive agents: dose adjustment may be required ( 7.3 )
• Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa ( 7.4 )
• Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of carbidopa, levodopa and entacapone tablets ( 7.5 , 7.6 , 7.7 , 7.8 , 7.9 )
• Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of carbidopa, levodopa and entacapone tablets may be required ( 7.10 )
• Drugs metabolized by CYP2C9 (e.g., coumadin): dose adjustment of carbidopa, levodopa and entacapone tablets may be required; monitor INR when initiating carbidopa, levodopa and entacapone tablets in patients on coumadin ( 7.11 ) 7.1 MAO Inhibitors Patients receiving nonselective MAO inhibitors and carbidopa, levodopa and entacapone may be at risk of increased adrenergic tone. Therefore, the use of carbidopa, levodopa and entacapone tablets is contraindicated in patients receiving nonselective MAO inhibitors [see Contraindications (4) ].

7.2 Drugs Metabolized by Catechol-O-Methyltransferase (COMT) Drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure [see Warnings and Precautions (5.11) ].

7.3 Antihypertensive Agents Symptomatic postural hypotension has occurred when carbidopa/levodopa was added to the treatment of patients receiving antihypertensive drugs. When starting therapy with carbidopa, levodopa and entacapone tablets, dosage adjustment of antihypertensive drug may be required.

7.4 Tricyclic Antidepressants There have been reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa.

7.5 Dopamine D2 Receptor Antagonists Dopamine D2 receptor antagonists (e.g., metoclopramide, phenothiazines, butyrophenones, risperidone) may reduce the therapeutic effects of levodopa.

7.6 Isoniazid Isoniazid may reduce the therapeutic effects of levodopa, a dose increase may be necessary.

7.7 Phenytoin The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Patients taking phenytoin with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Carbidopa, levodopa and entacapone tablets dosage should be increased as clinically needed in patients receiving phenytoin.

7.8 Papaverine The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by papaverine. Patients taking papaverine with carbidopa/levodopa should be carefully observed for loss of therapeutic response. Carbidopa, levodopa and entacapone tablets dosage should be increased as clinically needed in patients receiving papaverine.

7.9 Iron Salts Iron salts or multi vitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa, carbidopa and entacapone and consequently reduce bioavailability of levodopa, carbidopa and entacapone.

7.10 Drugs Known to Interfere with Biliary Excretion, Glucuronidation, and Intestinal Beta-glucuronidase As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol).

7.11 Drugs Metabolized via CYP2C9 (e.g., coumadin) The dosage of carbidopa, levodopa and entacapone tablets should be adjusted as clinically needed in patients using other drugs metabolized via CYP2C9. An interaction study in healthy volunteers, entacapone increased the AUC of R-warfarin on average by 18%, and the INR values on average by 13%. Cases of increased INR in patients concomitantly using warfarin have been reported during the post-approval use of entacapone. Thus, monitoring of INR is recommended when carbidopa, levodopa and entacapone tablets treatment is initiated for patients receiving warfarin.

• Pregnancy: based on animal data, may cause fetal harm ( 8.1 )

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

8.2 Lactation Risk Summary Levodopa has been detected in human milk after administration of carbidopa-levodopa. There are no data on the presence of entacapone or carbidopa in human milk, the effects of levodopa, carbidopa, or entacapone on the breastfed infant, or the effects on milk production. However, inhibition of lactation may occur because levodopa decreases secretion of prolactin [see Clinical Pharmacology ( 12.6 )]. Carbidopa and entacapone are excreted in rat milk. In lactating rat, oral administration of radiolabeled entacapone resulted in levels of entacapone and/or metabolites in milk up to 2 to 3 times that in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for carbidopa, levodopa and entacapone tablets and any potential adverse effects on the breastfed infant from carbidopa, levodopa and entacapone tablets or from the underlying maternal condition.

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

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

8.6 Renal Impairment Renal impairment does not affect pharmacokinetics of entacapone. There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment [see Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment or Biliary Obstruction There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment. Carbidopa, levodopa and entacapone tablets should be administered cautiously to patients with biliary obstruction or hepatic disease since biliary excretion appears to be the major route of excretion of entacapone and hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone [see Clinical Pharmacology (12.3) ].

Levodopa Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. However, levodopa the metabolic precursor of dopamine, does cross the blood-brain barrier, and is presumably converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson's disease. Carbidopa When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Entacapone Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3‑methoxy‑4‑hydroxy‑L‑phenylalanine (3‑OMD).