Carbidopa, Entacapone and Levodopa

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.

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.

Carbidopa, levodopa and entacapone tablets should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with carbidopa, levodopa and entacapone tablets if a decision has been made to add entacapone. Therapy should be individualized and adjusted according to the desired therapeutic response. • Evaluate vitamin B6 levels prior to starting treatment with carbidopa/levodopa therapies. • The optimum daily dosage of carbidopa, levodopa and entacapone tablets must be determined by careful titration in each patient. • Individual tablets should not be split or fractionated. Administer only one tablet at each dosing interval

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. • Narrow-angle glaucoma

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. • May cause syncope and hypotension/orthostatic hypotension. • May cause or exacerbate dyskinesia. • May cause depression and suicidality. • May cause hallucinations and/or other psychotic-like behavior. • May cause problems with impulse control and compulsive behaviors. • Abrupt discontinuation may cause hyperpyrexia and confusion. • May cause diarrhea and/or drug-induced colitis. • May cause rhabdomyolysis

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 • Hypotension/Orthostatic Hypotension and Syncope • Dyskinesia • Depression and suicidality • Hallucinations/Psychotic-Like Behavior • Impulse Control and/or Compulsive Behaviors • Withdrawal-Emergent Hyperpyrexia and Confusion • Diarrhea and Colitis • Rhabdomyolysis • Vitamin B6 Deficiency and Seizures • Peptic Ulcer Disease The most common adverse reactions (incidence 3% higher than placebo incidence) are dyskinesias, hyperkinesia, diarrhea, nausea, abdominal pain, vomiting, dry mouth and urine discoloration

• Drugs metabolized by COMT: use with caution. • Anti-hypertensive agents: dose adjustment may be required. • Tricyclic antidepressants: risk of hypertension and dyskinesia reported during concomitant use with carbidopa/levodopa. • Dopamine D2 receptor antagonists, isoniazid, phenytoin, papaverine and iron salts: may reduce efficacy of carbidopa, levodopa and entacapone tablets. • Drugs that interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase: dose adjustment of carbidopa, levodopa and entacapone tablets may be required. • 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

Store at 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).