Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following six strengths: Carbidopa, levodopa and entacapone film coated tablets 12.5 mg/50 mg/200 mg containing 12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone. Brown coloured, round shaped, biconvex, film coated tablets debossed with "M 71" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-491-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-491-12 Carbidopa, levodopa and entacapone film coated tablets 18.75 mg/75 mg/200 mg containing 18.75 mg of carbidopa, 75 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 72" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-492-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-492-12 Carbidopa, levodopa and entacapone film coated tablets 25 mg/100 mg/200 mg containing 25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 73" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-493-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-493-12 Carbidopa, levodopa and entacapone film coated tablets 31.25 mg/125 mg/200 mg containing 31.25 mg of carbidopa, 125 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 74" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-494-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-494-12 Carbidopa, levodopa and entacapone film coated tablets 37.5 mg/150 mg/200 mg containing 37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 75" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-495-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-495-12 Carbidopa, levodopa and entacapone film coated tablets 50 mg/200 mg/200 mg containing 50 mg of carbidopa, 200 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 70" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-496-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-496-12 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in tight container (USP).; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Carbidopa, Levodopa and Entacapone Tablets 12.5 mg, 50 mg and 200 mg Bottle of 100 Tablets NDC 33342-491-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 18.75 mg, 75 mg and 200 mg Bottle of 100 Tablets NDC 33342-492-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 25 mg, 100 mg and 200 mg Bottle of 100 Tablets NDC 33342-493-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 31.25 mg, 125 mg and 200 mg Bottle of 100 Tablets NDC 33342-494-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 37.5 mg, 150 mg and 200 mg Bottle of 100 Tablets NDC 33342-495-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 50 mg, 200 mg and 200 mg Bottle of 100 Tablets NDC 33342-496-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 12.5 mg, 50 mg and 200 mg Carton of 100 Tablets NDC 33342-491-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 18.75 mg, 75 mg and 200 mg Carton of 100 Tablets NDC 33342-492-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 25 mg, 100 mg and 200 mg Carton of 100 Tablets NDC 33342-493-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 31.25 mg, 125 mg and 200 mg Carton of 100 Tablets NDC 33342-494-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 37.5 mg, 150 mg and 200 mg Carton of 100 Tablets NDC 33342-495-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 50 mg, 200 mg and 200 mg Carton of 100 Tablets NDC 33342-496-12 Rx only cle-50-200mg-container cle-75-200mg-container cle-100-200mg-container cle-125-200mg-container cle-150-200mg-container cle-200-200mg-container 50-carton 75 mg carton 100 mg carton 125 mg carton 150 mg carton 200 mg carton
- 16 HOW SUPPLIED/STORAGE AND HANDLING Carbidopa, levodopa and entacapone) is supplied as film-coated tablets for oral administration in the following six strengths: Carbidopa, levodopa and entacapone film coated tablets 12.5 mg/50 mg/200 mg containing 12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone. Brown coloured, round shaped, biconvex, film coated tablets debossed with "M 71" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-491-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-491-12 Carbidopa, levodopa and entacapone film coated tablets 18.75 mg/75 mg/200 mg containing 18.75 mg of carbidopa, 75 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 72" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-492-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-492-12 Carbidopa, levodopa and entacapone film coated tablets 25 mg/100 mg/200 mg containing 25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 73" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-493-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-493-12 Carbidopa, levodopa and entacapone film coated tablets 31.25 mg/125 mg/200 mg containing 31.25 mg of carbidopa, 125 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 74" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-494-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-494-12 Carbidopa, levodopa and entacapone film coated tablets 37.5 mg/150 mg/200 mg containing 37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 75" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-495-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-495-12 Carbidopa, levodopa and entacapone film coated tablets 50 mg/200 mg/200 mg containing 50 mg of carbidopa, 200 mg of levodopa, and 200 mg of entacapone. Brown coloured, oval shaped, biconvex, film coated tablets debossed with "M 70" on one side and plain surface on the other side. HDPE bottle of 100 tablets NDC 33342-496-11 100 Tablets (10 x 10 Unit-dose) NDC 33342-496-12 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in tight container (USP).
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Carbidopa, Levodopa and Entacapone Tablets 12.5 mg, 50 mg and 200 mg Bottle of 100 Tablets NDC 33342-491-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 18.75 mg, 75 mg and 200 mg Bottle of 100 Tablets NDC 33342-492-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 25 mg, 100 mg and 200 mg Bottle of 100 Tablets NDC 33342-493-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 31.25 mg, 125 mg and 200 mg Bottle of 100 Tablets NDC 33342-494-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 37.5 mg, 150 mg and 200 mg Bottle of 100 Tablets NDC 33342-495-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 50 mg, 200 mg and 200 mg Bottle of 100 Tablets NDC 33342-496-11 Rx only Carbidopa, Levodopa and Entacapone Tablets 12.5 mg, 50 mg and 200 mg Carton of 100 Tablets NDC 33342-491-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 18.75 mg, 75 mg and 200 mg Carton of 100 Tablets NDC 33342-492-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 25 mg, 100 mg and 200 mg Carton of 100 Tablets NDC 33342-493-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 31.25 mg, 125 mg and 200 mg Carton of 100 Tablets NDC 33342-494-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 37.5 mg, 150 mg and 200 mg Carton of 100 Tablets NDC 33342-495-12 Rx only Carbidopa, Levodopa and Entacapone Tablets 50 mg, 200 mg and 200 mg Carton of 100 Tablets NDC 33342-496-12 Rx only cle-50-200mg-container cle-75-200mg-container cle-100-200mg-container cle-125-200mg-container cle-150-200mg-container cle-200-200mg-container 50-carton 75 mg carton 100 mg carton 125 mg carton 150 mg carton 200 mg carton
Overview
Carbidopa, levodopa and entacapone tablets is a combination of carbidopa, levodopa, and entacapone for the treatment of Parkinson’s disease. Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(α-methyl-β-(3,4dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C 10 H 14 N 2 O 4 •H 2 O, and its structural formula is: Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3. Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C 9 H 11 NO 4 , and its structural formula is: Entacapone, a COMT inhibitor, is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C 14 H 15 N 3 O 5 and its structural formula is: Carbidopa, levodopa and entacapone film coated tablets is supplied as tablets in 6 strengths: 12.5 mg of carbidopa, USP; 50 mg of levodopa, USP and 200 mg of entacapone USP 18.75 mg of carbidopa, USP; 75 mg of levodopa, USP and 200 mg of entacapone USP 25 mg of carbidopa, USP; 100 mg of levodopa, USP and 200 mg of entacapone USP 31.25 mg of carbidopa, USP; 125 mg of levodopa, USP and 200 mg of entacapone USP 37.5 mg of carbidopa, USP; 150 mg of levodopa, USP and 200 mg of entacapone USP 50 mg of carbidopa, USP; 200 mg of levodopa, USP and 200 mg of entacapone USP Inactive Ingredients: Colloidal silicon dioxide, Croscarmellose sodium, Crospovidone, Magnesium stearate, Maltodextrin, Microcrystalline cellulose, Povidone. The coating material Instacoat Brown HIS consists of Hypromellose, Polysorbate 80, Red Iron Oxide, Titanium Dioxide, Yellow Iron Oxide cle-str-carb.jpg cle-str-levo.jpg cle-str-enta.jpg
Indications & Usage
INDICATIONS & USAGE Carbidopa, levodopa and entacapone tablets, is 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 “wearingoff” and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias ( 1 )
Dosage & Administration
DOSAGE & ADMINISTRATION 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 (see below). Therapy should be individualized and adjusted according to the desired therapeutic response. • The optimum daily dosage of Carbidopa, levodopa and entacapone tablets must be determined by careful titration in each patient ( 2.1 ) • Individual tablets should not be split or fractionated. Administer only one tablet at each dosing interval ( 2.6 ) 2.1 Dosing Information The optimum daily dosage of Carbidopa, levodopa and entacapone tablets must be determined by careful titration in each patient. Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of Carbidopa, levodopa and entacapone tablets depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (Carbidopa, levodopa and entacapone tablets 200) than with lower strengths (see Table 1). Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting. Table 1: Maximum Recommended Dose of Carbidopa, levodopa and entacapone tablets in a 24-hour Period Carbidopa, levodopa and entacapone tablets Dosage Strength Maximum Number of Tablets in a 24-hour Period 12.5 mg /50 mg /200 mg18.75 mg /75 mg /200 mg 25 mg /100 mg /200 mg31.25mg /125mg /200 mg37.5 mg /150 mg /200 mg 8 50 mg/200 mg/200 mg 6 2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Carbidopa, levodopa and entacapone tablets Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of carbidopa, levodopa and entacapone tablets containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single carbidopa, levodopa and entacapone 25 mg/100 mg/200 mg tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone). 2.3 Converting Patients from Carbidopa and Levodopa Products to Carbidopa, levodopa and entacapone tablets There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa. Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient’s individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of Carbidopa, levodopa and entacapone tablets. When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of Carbidopa, levodopa and entacapone tablets at each administration or by decreasing the frequency of administration by extending the time between doses. 2.4 Concomitant Use with Other Anti-Parkinson’s Disease Drugs Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) -B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while Carbidopa, levodopa and entacapone tablets is being administered; however, dosage adjustments of the concomitant medication or Carbidopa, levodopa and entacapone tablets may be required. 2.5 Decrease or Interruption of Dosing Avoid interruption of Carbidopa, levodopa and entacapone tablets dosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [see Warnings and Precautions ( 5.7 )]. 2.6 Important Administration Instructions Do not split, crush or chew Carbidopa, levodopa and entacapone tablets. Administer only one tablet at each dosing interval. All strengths of Carbidopa, levodopa and entacapone tablets contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone. Administer Carbidopa, levodopa and entacapone tablets with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [see Clinical Pharmacology ( 12.3 )].
Warnings & Precautions
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 ( 2.5 ) 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 ( 2.5 ), 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 ( 2.5 )]. Specific methods for tapering entacapone have not been systematically evaluated. 5.8 Diarrhea and Colitis In clinical trials of entacapone, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg of entacapone or placebo in combination with levodopa and dopa decarboxylase inhibitor, respectively. In patients treated with entacapone, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of entacapone. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia. Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when entacapone treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of entacapone but recurred after retreatment with entacapone. If prolonged diarrhea is suspected to be related to Carbidopa, levodopa and entacapone tablets, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered. 5.9 Rhabdomyolysis Cases of severe rhabdomyolysis have been reported with entacapone when used in combination with carbidopa and levodopa. Severe prolonged motor activity including dyskinesia may possibly account for rhabdomyolysis. Most of the cases were manifested by myalgia and increased values of creatine phosphokinase (CPK) and myoglobin. Some of the reactions also included fever and/or alteration of consciousness. It is also possible that rhabdomyolysis may be a result of the syndrome described in Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.7 )]. 5.10 Interaction with Drugs Metabolized by 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 rate, arrhythmia, and/or increased blood pressure. 5.11 Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse reactions may be related to the ergoline structure of these compounds, a possible causal role of nonergot derived drugs (e.g., entacapone, levodopa), which increase dopaminergic activity, has also been considered. The expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone during its clinical development. Four cases of pulmonary fibrosis have been reported during clinical development of entacapone; 3 of these patients were also treated with pergolide and 1 with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months. 5.12 Peptic Ulcer Disease As with levodopa, treatment with Carbidopa, levodopa and entacapone tablets may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. 5.13 Hepatic Impairment Patients with hepatic impairment should be treated with caution [see Clinical Pharmacology ( 12.3 )]. As with levodopa, periodic evaluation of hepatic function is recommended during extended therapy. 5.14 Laboratory Tests Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Carbidopa, levodopa and entacapone tablets than with levodopa. Carbidopa, levodopa and entacapone tablets may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. Cases of falsely diagnosed pheochromocytoma in patients on carbidopa/levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa/levodopa therapy.
Contraindications
Carbidopa, levodopa and entacapone tablets is 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 )
Adverse Reactions
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) ] 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 Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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 Adverse Reaction Carbidopa/levodopa plus Entacapone (n=603) % of patients Carbidopa/levodopa plus Placebo (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 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.
Drug Interactions
• 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 ( 5.10 )]. 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.
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