Data from FDA - Curated by EPG Health - Last updated 22 August 2017

Indication(s)

1 INDICATIONS AND USAGE Carbidopa, levodopa and entacapone tablets, a combination drug consisting of levodopa, carbidopa (dopa decarboxylase inhibitor), and entacapone (catechol-O-methyltransferase-COMT inhibitor) is indicated for the treatment of Parkinson’s disease. Carbidopa, levodopa and entacapone tabletscan 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 are 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)

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Advisory information

contraindications
4 CONTRAINDICATIONS 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)
Adverse reactions
6 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% or higher than placebo incidence) are dyskinesias, urine discoloration, diarrhea, nausea, abdominal pain, vomiting, and dry mouth (6) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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, urine discoloration, diarrhea, nausea, hyperkinesia, vomiting, and dry mouth. 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 Preferred Term 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.

Usage information

Dosing and administration
2 DOSAGE AND 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 50 mg/200 mg/200 mg) 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 mg 18.75 mg/75 mg/200 mg 25 mg/100 mg/200 mg 31.25 mg/125 mg/200 mg 37.5 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 tablet 25 mg/100 mg/200 mg (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. 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 are being administered; however, dosage adjustments of the concomitant medication or carbidopa, levodopa and entacapone tabletsmay be required. 2.5 Decrease or Interruption of Dosing Avoid interruption of carbidopa, levodopa and entacapone tabletsdosing 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animals, administration of carbidopa-levodopa or entacapone during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations. Carbidopa, levodopa and entacapone tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 8.3 Nursing Mothers Carbidopa and entacapone are excreted in rat milk. It is not known whether entacapone, carbidopa, or levodopa is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when carbidopa, levodopa and entacapone tablets are administered to a nursing woman. 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)].
Pregnancy and lactation
8.3 Nursing Mothers Carbidopa and entacapone are excreted in rat milk. It is not known whether entacapone, carbidopa, or levodopa is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when carbidopa, levodopa and entacapone tablets are administered to a nursing woman.

Interactions

7 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 (5.11)]. 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 tabletsshould 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.

More information

Category Value
Authorisation number NDA021485
Agency product number MNX7R8C5VO
Orphan designation No
Product NDC 47335-001,47335-002,47335-003,47335-004,47335-005,47335-006
Date Last Revised 08-05-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 730988
Marketing authorisation holder Sun Pharma Global FZE